Benzofuran derivatives useful as inhibitors of bone resorption

ABSTRACT

This invention relates to a novel heterocyclic compound represented by formula (I), wherein each symbol is as defined in the specification and a pharmaceutically acceptable salt thereof which are the inhibitors of bone resorption and bone metabolism, to processes for preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of diseases caused by abnormal bone metabolism in human being or an animal.

This application is a 371 of PCT/JP95/00787 filed Apr. 21, 1995.

TECHNICAL FIELD

The present invention relates to a novel heterocyclic compound and apharmaceutically acceptable salt thereof which are useful as amedicament.

BACKGROUND ART

In Japanese Patent Application Laid-open No.60-48924, No. 60-54379,etc., there are disclosed thionaphten-2-carboxylic acid derivatives and3-phenyl-4H-1-benzopyran-4-one derivatives inhibiting bone resorption.

DISCLOSURE OF INVENTION

The present invention relates to a novel heterocyclic compound and apharmaceutically acceptable salt thereof which are the inhibitors ofbone resorption, the inhibitors of bone metastases and useful for theprophylactic and/or therapeutic treatment of bone disease characterizedby abnormal bone metabolism such as osteoporosis (especially,postmenopausal osteoporosis); hyper-calcemia; hyperparathyroidism;Paget's bone diseases; osteolysis; hypercalcemia of malignancy with orwithout bone metastases; rheumatoid arthritis; periodontitis;osteoarthritis; ostealgia; osteopenia; cancer cachexia; or the like in ahuman being or an animal.

And further, the present invention relates to processes for thepreparation of the heterocyclic derivatives, to a pharmaceuticalcomposition comprising the same and to a method for the prophylacticand/or therapeutic treatment of above-mentioned diseases in a humanbeing or an animal, and to a use of the heterocyclic derivatives andpharmaceutically acceptable salts thereof for the prophylactic and/ortherapeutic treatment of above-mentioned diseases in human therapeutictreatment of above-mentioned diseases in human being or an animal.

The heterocyclic derivatives of this invention are new and can berepresented by the following general formula (I): ##STR2## wherein R¹ ishydrogen, lower alkyl, an acyl group, amino, acylamino, nitro, halogenor hydroxy(lower)alkyl which may have one or more suitablesubstituent(s),

R² is hydrogen, lower alkyl, an acyl group, lower alkoxy,acyl(lower)alkyl, aryl, cyano, mono-(or di- or tri-)-halo (lower)alkyl,lower alkylthio or hydroxy(lower)alkyl which may have one or moresuitable substituent(s),

R³ is hydrogen, lower alkyl, lower alkenyl,cyclo(lower)alkyl(lower)alkyl, halogen, an acyl group, acyl(lower)alkyl,acylamino, acylamino(lower)alkyl, acyl(lower)alkenyl,acyloxy(lower)alkyl, acyl(lower)alkylthio(lower)alkyl,amino(lower)alkyl, mono-(or di-)lower alkylamino, loweralkylthio(lower)alkyl, hydroxyimino(lower)alkyl which may have one ormore suitable substituent(s), hydroxy(lower)alkyl which may have one ormore suitable substituent(s), hydroxy(lower)alkylthio(lower)alkyl,cyano(lower)alkyl, mono-(or di-)lower alkoxy(lower)alkyl which may haveone or more suitable substituent(s), lower alkyl substituted with arylwhich may have one or more suitable substituent(s), mono-(or di-)loweralkylamino(lower)alkyl, lower alkyl substituted with heterocyclic groupwhich may have one or more suitable substituent(s), heterocyclic groupwhich may have one or more suitable substituent(s), heterocyclicthio,heterocyclicthio(lower),alkyl, heterocyclicoxy,heterocyclicoxy(lower)alkyl, heterocyclicaminoimino-(lower)alkyl, aryl,amino or nitro,

in which R² and R3 may be linked together to form

(1) lower alkylene which may have one or more suitable substituent(s),

(2) lower alkenylene which may have one or more suitable substituent(s),or

(3) a group of the formula ##STR3## wherein A¹ and A² are each loweralkylene which may have one or more suitable substituent(s) or loweralkenylene which may have one or more suitable substituent(s),

W is ##STR4## (wherein R⁵ is hydrogen, lower alkyl or an acyl group) andm and n are each integer of 0 or 1.!,

X is O or S,

Y is vinylene, or a group of the formula: ##STR5## (wherein R⁶ is loweralkyl), Z is heterocyclic group which may have one or more suitablesubstituent(s), or aryl which may have one or more suitablesubstituent(s),

l is an integer of 0 or 1, and --- is a single bond or a double bond,and a pharmaceutically acceptable salt thereof.

The object compound (I) or a salt thereof can be prepared by theprocesses as illustrated in the following reaction schemes. ##STR6##wherein R¹, R², R³, X, Y, Z , --- and l are each as defined above,

R_(a) ¹ is acylamino,

R_(b) ¹ is amino,

R_(a) ³ is lower alkyl substituted with oxo,

R_(b) ³ is hydroxy(lower)alkyl,

R_(c) ³ is acyloxy(lower)alkyl,

E is lower alkylene, lower alkenylene or a group of the formula:##STR7## R' is hydrogen or lower alkyl, R" is leaving group,

R"' is lower alkyl, cyclo(lower)alkyl, lower alkyl substituted withheterocyclic group which may have one or more suitable substituent(s),lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, amino, heterocyclicgroup, carboxy(lower)alkyl, protected carboxy(lower)alkyl, lower alkylsubstituted with aryl which may have one or more suitable substituent(s)or arylsulfonyl,

G¹ is --COOH or --SO₃ H,

G² is --CO-- or --SO₂ --,

X' is halogen,

m is an integer of 0 to 6, and

b, r, q and u are each an integer of 0 or 1.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salts and may include a salt with a base oran acid addition salt such as a salt with an inorganic base, forexample, an alkali metal salt (e.g., sodium salt, potassium salt, etc.),an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.),an ammonium salt; a salt with an organic base, for example, an organicamine salt (e.g., triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid additionsalt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); anorganic carboxylic or sulfonic acid addition salt (e.g., formate,acetate, trifluoroacetate, maleate, tartrate, fumarate,methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt witha basic or acidic amino acid (e.g., arginine, aspartic acid, glutamicacid, etc.).

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

The term "lower" is used to intend a group having 1 to 6 carbon atom(s),unless otherwise provided.

The term "higher" is used to intend a group having 7 to 20 carbon atoms,unless otherwise provided.

Suitable example of "one or more" may be the number of 1 to 6, in whichthe preferred one may be the number of 1 to 4.

Suitable "lower alkyl" and "lower alkyl moiety" may include straight orbranched one having 1 to 6 carbon atom(s), such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and thelike, preferably one having 1 to 5 carbon atom(s).

Suitable "lower alkenyl" and "lower alkenyl moiety" may include vinyl,1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)-hexenyl, methylvinyl,ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or3-)ethyl-1-(or 2-)propenyl, 1-(or 2-or 3- or 4-)methyl-1-(or 2- or3-)butenyl, and the like, in which more preferable example may be (C₂-C₄)alkenyl, and the most preferred one may be methylvinyl.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy isopropoxy,butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and thelike.

Suitable "aryl" and "aryl moiety" may include phenyl, naphthyl, anthryland the like.

Suitable "leaving group" may include acid residue and the like, andsuitable examples of "acid residue" may be halogen (e.g., fluorine,chlorine, bromine, iodine.), acyloxy e.g., sulfonyloxy (e.g.,phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g.,acetyloxy, propionyloxy, etc.), etc.!, lower alkyl (e.g., methyl, ethylpropyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl,t-pentyl, hexyl, etc.), aryl (e.g., phenyl, naphthyl, anthryl, etc.),ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl,phenylpropyl, etc.), di(lower)alkylamino (e.g., dimethylamino,diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino,ethylmethylamino, ethylpropylamino, etc.), loweralkyl(lower)alkoxyamino(e.g., methylmethoxyamino, methylethylamino,ethylmethoxyamino, ethylethoxyamino, etc.) or the like.

Suitable "acid residue" may include halogen (e.g., fluorine chlorine,bromine, iodine, etc.), acyloxy e.g., sulfonyloxy (e.g.,phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g.,acetyloxy, propionyloxy, etc.), etc.! and the like.

Suitable "lower alkylene" may include straight or branched one such asmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, methylmethylene, ethylethylene, ethylpropylene, and thelike.

Suitable "lower alkenylene" may include straight or branched one having2 to 6 carbon atoim(s) such as vinylene, propenylene, 1-(or2-)butenylene, 1-(or 2- or 3-)pentenylene, 1-(or 2- or 3-)hexenylene,methylvinylene, ethylvinylene, 1-(or 2- or 3-)methylpropenylene, 1-(or2- or 3-)-ethylpropenylene, 1-(or 2- or 3- or 4-)methyl-1-(or2-)-butenylene, and the like.

Suitable "cyclo(lower)alkyl" may include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like, in which the preferred one may becyclo(C₄ -C₆)alkyl.

Suitable "halogen" and "halo" moiety may include fluorine, bromine,chlorine, and iodine.

Suitable "an acyl group" and "acyl" moiety may include carbamoyl,aliphatic acyl group and acyl group containing an aromatic ring, whichis referred to as aromatic acyl, or heterocyclic ring, which is referredto as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows :

carbamoyl; carboxy; aliphatic acyl such as lower or higher alkanoyl(e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl,nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl,pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl,icosanoyl, etc.); cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.);protected carboxy such as commonly protected carboxy e.g., esterifiedcarboxy such as lower or higher alkoxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propyloxycarbonyl, iso-propyloxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), etc.!,or the like; lower or higher alkylsulfonyl (e.g., methylsulfonyl,ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g.,methcxysulfonyl, ethoxysulfonyl, etc.); di-(lower)alkoxyphosphoryl(e.g., dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl,dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.),a group of the formulas: ##STR8## (wherein A⁴ and A⁵ are lower alkylene,amino(lower)alkylene or aminophenylene,

R¹¹ is lower alkyl or hydrogen and

S and t are each integer of 1 to 6, or the like);

aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);ar(lower)alkanoyl e.g., phenyl(lower)alkanoyl (e.g., Phenylacetyl,phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl,naphthylpropanoyl, naphthylbutanoyl, etc.), etc.!; ar(lower)alkenoyle.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl,phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl,etc.), etc.!; ar(lower)alkoxycarbonyl e.g., phenyl(lower)alkoxycarbonyl(e.g. benzyloxycarbonyl, etc.), etc.!; aryloxycarbonyl (e.g.,phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl(e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylcarbamoyl (e.g.,phenylcarbamoyl, etc.); arylthiocarbamoyl (e.g., phenylthiocarbamoyl,etc.); arylglyoxyloyi (e.g., phenylglyoxyloyl, naphthylglyoxyloyl,etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); orthe like.

heterocyclic acyl such as

heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g.,heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl,heterocyclicpentanoyl, heterocyclichexanoyl, etc.);

heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl,heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl,etc.); heterocyclicglyoxyloyl; or the like; and the like.

Suitable "heterocyclic group" and "heterocyclic moiety" may includesaturated or unsaturated monocyclic or polycyclic heterocyclic groupcontaining at least one hetero-atom such as an oxygen, sulfur, nitrogenatom and the like.

And, especially preferable one may be heterocyclic group such as

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,phthalimidyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,pyranyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s), for example,oxiranyl, oxolanyl, dioxolanyl, tetrahydrofuranyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfurarom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 oxygenatom(s), for example, methylenedioxyphenyl, benzodioxanyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like,

and "heterocyclic group" and "heterocyclic moiety" as stated above mayhave one or more suitable substituent(s) such as oxo; halogen (e.g.,fluorine, chlorine, bromine, iodine, etc.); lower alkanoyl (e.g.,formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl, etc.); aryl (e.g., phenyl, naphthyl,anthryl, etc.); lower alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, isopentyl,tert-pentyl, neopentyl, hexyl, isohexyl, etc.); and the like.

The acyl moiety as stated above may have one to ten, same or different,suitable substituent(s) such as lower alkyl (e.g., methyl, ethyl,propyl, etc.); lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.);lower alkylthio (e.g., methylthio, ethylthio, etc.); mono-(or di-)loweralkylamino (e.g., methylamino, ethylamino, propylamino, dimethylamino,diethylamino, dipropylamino, etc.); lower alkanoylamino (e.g.,acetylamino, propionylamino, butyrylamino, pentanoylamino,hexanoylamino, etc.); cyclo(lower)alkylamino (e.g., cyclopropylamino,cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.); mono-(ordi-)lower alkoxy(lower)alkylamino (e.g., methoxymethylamino,methoxyethylamino, methoxypropylamino, ethoxymethylamino,ethoxyethylamino, ethoxypropylamino, etc.); hydroxy(lower)alkylamino(e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypentyl,hydroxyhexyl, etc.); heterocyclic(lower)alkylamino, in which"heterocyclic moiety" is aforementioned "heterocyclic" moiety;heterocyclicamino which may have one or more suitable substituent(s), inwhich "heterocyclic" moiety is aforementioned "heterocyclic" moiety;lower alkanoyloxy (e.g., acetyloxy, propionyloxy, butyryloxy,pentanoyloxy, hexanoyloxy, etc.); heterocyclic group, in which"heterocyclic group" is aforementioned "heterocyclic group"; di-loweralkoxy(lower)alkyl (e.g., dimethoxymethyl, dimethoxyethyl,dimethoxypropyl, diethoxymethyl, diethoxyethyl, diethoxypropyl, etc.);arylamino which may have one or more suitable substituent(s) (e.g.,phenylamino, dimethylaminophenylamino, trifluoromethylphenylamino,trifluoromethylnaphthylamino, trifluoromethylanthrylamino, etc.);cyano(lower)alkylamino (e.g., cyanomethylamino, cyanoethylamino,cyanopropylamino, cyanobutylamino, cyanopentylamino, cyanohexylamino,etc.); arylsulfonylamino (e.g., phenylsulfonylaminonaphthylsulfonylamino, anthrylsulfonylamino, etc.); protectedcarboxy(lower)alkylamino (e.g., methoxycarbonylmethylamino,methoxycarbonylethylamino, ethoxycarbonylmethylamino,ethoxycarbonylethylamino, etc.); tri-halo(lower)alkylamino (e.g.,2,2,2-trifluoroethylamino, 1-(trifluoromethyl)ethylamino,2-(trifluoromethyl)propylamino, etc.); cyclo(lower)alkyl (e.g.,cyclopentyl, cyclohexyl, etc.); cyclo(lower)alkenyl (e.g., cyclohexenyl,cyclohexadienyl, etc.); halogen (e.g., fluorine, chlorine, bromine,iodine, etc.); amino, commonly protected amino as mentioned above;hydroxy; commonly protected hydroxy as mentioned below; cyano; nitro;carboxy; carboxy(lower)alkyl; commonly protected carboxy as mentionedbelow; sulfo; sulfamoyl; imino; oxo; hydrazino; amino(lower)alkyl (e.g.,aminomethyl, aminoethyl, etc.); carbamoyloxy; hydroxy(lower)alkyl (e.g.,hydroxymethyl, 1-(or 2-)hydroxyethyl, 1-(or 2- or 3-)hydroxypropyl,etc.), or the like.

Suitable "hydroxy protective group" in the term commonly "protectedhydroxy" may include acyl as mentioned above, phenyl(lower)alkyl whichmay have one or more suitable substituent(s) (e.g., benzyl,4-methoxybenzyl, trityl, etc.), trisubstituted silyl e.g.,tri(lower)alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.),etc.!, tetrahydropyranyl and the like.

Suitable commonly "protected carboxy" may include esterified carboxy andthe like. And suitable example of said ester may be the ones such aslower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester,isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentylester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g.,vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynylester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g.,methoxymethyl ester, ethoxymethyl ester, isopropoxy ester,1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); loweralkylthio(lower)alkyl ester (e.g., methylthiomethyl ester,ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl ester,etc.); mono-(or di- or tri-)halo(lower)alkyl ester (e.g., 2-iodoethylester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkylester (e.g., acetoxymethyl ester, propionyloxymethyl ester,butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester,2-propionyloxyethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkylester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethylester, propoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxy!ethyl ester, 1-(or 2-) Lethoxycarbonyloxy!ethylester, 1-(or 2-) propoxycarbonyloxy!ethyl ester, 1-(or 2-)isopropoxycarbonyloxy!ethyl ester, etc.); loweralkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesyethylester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g.,methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester,propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester,1-(or 2-)propoxycarbonyloxyethyl ester, 1-(or2-)isopropoxycarbonyloxyethyl ester, etc.); phthalidylidene(lower)alkylester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester e.g.,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.!; ar(lower)alkylester, for example, phenyl(lower)alkyl ester which may have one or moresuitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester,4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may haveone or more suitable substituent(s) such as substituted or unsubstitutedphenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester,xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester,4-methoxyphenyl ester, etc.); tri(lower)alkyl silyl ester; loweralkylthioester (e.g., methylthioester, ethylthioester, etc.) and thelike.

The preferred examples of "an acyl group" may be carboxy protectedcarboxy, carbamoyl, lower alkanoyl, lower alkylsulfonyl, aroyl,heterocyclic carbonyl which may have one or more suitablesubstituent(s), in which the more preferred one may be carboxy, (C₁-C₄)alkoxy carbonyl, carbamoyl, (C₁ -C₄)alkanoyl, (C₁ -C₄)alkylsulfonyl,benzoyl, carbonyl substituted with unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), carbamoylsubstituted with saturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), carbonylsubstituted with saturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s) having (C₁ -C₄)alkyl, and the mostpreferred one may be carboxy, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, carbamoyl, acetyl, methylsulfonyl, benzoyl,morpholinocarbonyl, N-methylpiperidylcarbonyl or pyridylcarbonyl.

Suitable "acyl" moiety in the term of "acylamino" can be referred toaforementioned "acyl" moiety.

The preferred examples of "acylamnino" may be ureido, loweralkanoylamino, lower alkoxycarbonylamino, heterocyclic carbonylamino,lower alkanoylamino(lower)alkanoylamino (e.g. acetylaminoacetylamino,acetylaminopropionylamino, propionylaminoacetylamino,propionylaminopropionylamino, etc.), mono-(or di-)loweralkylamino(lower)alkanoylamino (e.g., methylaminoacetylamino,dimethylaminoacetylamino, ethylaminoacetylamino,diethylaminoacetylamino, etc.), lower alkanoyloxy(lower)alkanoylaminoe.g., acetyloxyacetylamino, acetyloxypropionylamino,propionyloxyacetylamino, propionyloxypropionylamino, etc.),heterocyclic(lower)alkanoylamino (e.g., heterocyclic-carbonylamino,heterocyclic-acetylamino, heterocyclic-propionylamino, etc.), loweralkoxy(lower)alkanoylamino (e.g., methoxyacetylamino, ethoxyacetylamino,methoxypropionylamino, ethoxypropionylamino, etc.),hydroxy(lower)alkanoylamino (e.g., hydroxyacetylamino,hydroxypropionylamino, etc.), lower alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, etc.), ormono-(or di-)lower alkoxy(lower)alkylamino(lower)-alkanoylamino (e.g.,methoxymethylaminoacetylamino, bis(methoxymethyl)aminoacetylamino,methoxyethylaminoacetylamino, bis(methoxyethyl)aminoacetylamino, etc.),in which the more preferred one may be ureido, (C₁ -C₄)alkanoylamino,(C₁ -C₄)-alkoxycarbonylamino, carbonylamino substituted with saturated 3to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s)and 1 to 3 nitrogen atom(s), (C₁ -C₄)-alkanoylamino (C₁-C₄)alkanoylamino, di(C₁ -C₄)alkylamino-(C₁ -C₄) alkanoylamino, (C₁-C₄)alkanoyloxy(C₁ -C₄)alkanoylamino, (C₁ -C₄)alkanoylamino substitutedwith saturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), (C₁ -C₄)alkoxy(C₁-C₄)-alkanoylamino, hydroxy(C₁ -C₄)alkanoylamino, (C₁-C₄)-alkylsulfonylamino or bis (C₁ -C₄)alkoxy(Cl-C₄)alkyl!amino (C₁-C₄)alkanoylamino and the most preferred one may be ureido, acetylamino,t-butoxycarbonylamino, morpholinocarbonylamino, acetylaminoacetylamino,dimethylaminoacetylamino, acetyloxyacetylamino, morpholinoacetylamino,methoxyacetylamino, hydroxyacetylamino, methylsulfonylamino ordimethoxyethylaminoacetylamino.

Suitable "hydroxy(lower)alkyl" may be hydroxymethyl, 1-(or2-)hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxypropyl,1-hydroxy-1-ethylethyl, 1-hydroxy-1-ethylpropyl, 1-hydroxybutyl, 1-(or2- or 3-)hydroxy-1-(or 2- or 3-)methylpropyl, 1-(or 2- or 3- or4-)hydroxy-1-(or 2- or 3- or 4-)methylbutyl, 1-(or 2- or 3- or 4- or5-)hydroxy-1-(or 2- or 3- or 4- or 5-)methylpentyl, 1-(or 2- or 3- or 4-or 5- or 6-)hydroxy-1-(or 2- or 3- or 4- or 5- or 6-)-methylhexyl, orthe like.

The preferred examples of "hydroxy(lower)alkyl" may be hydroxy(C₁-C₅)alkyl, and the most preferred one may be hydroxymethyl,1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxy-1-ethylpropyl,1-hydroxybutyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 1-hydroxybutyl,2-hydroxypropyl or 2-hydroxy-2-methylpropyl.

The preferred examples of "suitable substituent(s)" in the term of"hydroxy(lower)alkyl which may have one or more suitable substituent(s)"may be mono-(or di- or tri-)-halo (lower)alkyl, protected carboxy,hydroxy, aryl, cyclo(lower)alkyl or heterocyclic group, in which thepreferred one may be tri-halo(C₁ -C₄)alkyl, (C₁ -C₄)-alkoxycarbonyl,hydroxy, phenyl, cyclo(C₃ -C₆)alkyl, or unsaturated heteromonocyclicgroup consisting of 1 to 4 nitrogen atom(s), and the most preferred onemay be trifluoromethyl, ethoxycarbonyl, hydroxy, phenyl, cyclohexyl orpyridyl.

Suitable "acyl" moiety in the term of "acyl(lower)alkyl" can be referredto aforementioned "acyl" moiety.

The preferred examples of "acyl(lower)alkyl" may be carboxy(lower)alkyl,protected carboy(lower)alkyl, carbamoyl(lower)alkyl, loweralkanoyl(lower)alkyl, aroyl(lower)alkyl, carbonyl(lower)alkylsubstituted with heterocyclic group which may have one or more suitablesubstituent(s), lower alkyl having ##STR9## (wherein A⁴ is loweralkylene, amino lower alkylene or aminophenylene,

R¹¹ is lower alkyl or hydrogen, and

s and t are each integer of 1 to 6),

(mono- or di-)lower alkylamino)carbonyl(lower)alkyl which may have oneor more suitable substituent(s) (e.g., methylaminocarbonylmethyl,dimethylaminocarbonylmethyl, methylaminocarbonylethyl,2-dimethylaminocarbonylethyl, trifluoromethylaminocarbonylmethyl,trifluoroethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl,cyanoethylcarbonylmethyl, cyanomethylcarbonylethyl, etc.),cyclo(lower)alkylaminocarbonyl(lower)alkyl (e.g.cyclopropylaminocarbonylmethyl, cyclobutylaminocarbonylmethyl,cyclopentylaminocarbonylmethyl, cyclohexylaminocarbonylmethyl, etc.),lower alkoxy(lower)alkylaminocarbonyl(lower)alkyl (e.g.,methoxymethylaminocarbonylmethyl, methoxyethylaminocarbonylmethyl,bis(methoxymethylamino)carbonylmethyl,bis(methoxyethylamino)carbonylmethyl, etc.), di-(lower)alkoxyphosphoryl(e.g., dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl,dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.),mono-(or di-)hydroxy(lower)alkylaminocarbonyl(lower)alkyl (e.g.,hydroxymethylaminocarbonylmethyl, hydroxyethylaminocarbonylmethyl,dihydroxymethylaminocarbonylmethyl, dihydroxyethylaminocarbonylmethyl,etc.), aminocarbonyl(lower)alkyl substituted with heterocyclic groupwhich may have one or more suitable substituent(s) (e.g.thiazolylaminocarbonylmethyl, pyridylaminocarbonylmethyl,morpholinoaminomethyl, methyloxadiazolylaminocarbonylmethyl,trifluorothiadiazolylaminocarbonylmethyl, etc.),heterocyclic(lower)alkylaminocarbonyl(lower)alkyl (e.g.,pyridylmethylaminocarbonylmethyl,tetrahydrofuranylmethylaminocarbonvlmethyl, etc.),hydrazinocarbonyl(lower)alkyl (e.g., hydrazinocarbonylmethyl,hydrazinocarbonylethyl, hydrazinocarbonylpropyl, etc.),aminocarbonyl(lower)alkyl substituted with aryl which may have one ormore suitable substituent(s) (e.g.,dimethylaminophenylaminocarbonylmethyl,trifluoromethylphenylaminocarbonylmethyl, etc.),cyano(lower)alkylaminocarbonyl(lower)alkyl (e.g.,cyanomethylaminocarbonylmethyl, cyanoethylaminocarbonylmethyl,cyanomethylaminocarbonylethyl, cyanoethylaminocarbonylethyl, etc.),arylsulfonylaminocarbonyl(lower)alkyl (e.g.,phenylsulfonylaminocarbonylmethyl, phenylsulfonylaminocarbonylethyl,phenylsulfonylaminocarbonylpropyl, etc.), protectedcarboxy(lower)alkylaminocarbonyl(lower)alkyl (e.g.methoxycarbonylmethylaminocarbonylmethyl,ethoxycarbonylmethylaminocarbonylmethyl,methoxycarbonylmethylaminocarbonylethyl,ethoxycarbonylmethylaminocarbonylethyl, etc.), in which the preferredone may be (C₁ -C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, (C₁ -C₄)alkanoyl(C₁-C₄)alkyl, carbamoyl-(C₁ -C₄)alkyl, carboxy(C₁ -C₄)alkyl, lower alkylhaving ##STR10## (wherein A⁴ is (C₁ -C₆)alkylene, amino(C₁ -C₆)alkyleneor aminophenylene,

R¹¹ is (C₁ -C₆)alkyl or hydrogen, and

s and t are each integer of 1 to 6),

carbonyl(C₁ -C₄)alkyl substituted with heterocyclic group which may have1 to 3 suitable substituent(s), mono-(or di-)(C₁-C₄)alkylaminocarbonyl(C₁ -C₄)alkyl which may have 1 to 3 suitablesubstituent(s), cyclo(C₃ -C₆)alkylaminocarbonyl(C₁ -C₄)alkyl, (C₁-C₄)alkoxy(C₁ -C₄)alkylaminocarbonyl(C₁ -C₄)alkyl, di-(C₁-C₄)alkoxyphosphoryl(C₁ -C₄)alkyl, mono-(or di-)hydroxy(C₁-C₄)alkylaminocarbonyl(C₁ -C₄)alkyl, aminocarbonyl(C₁ -C₄)alkylsubstituted with heterocyclic group which may have 1 to 3 suitablesubstituent(s), heterocyclic(C₁ -C₄)alkylaminocarbonyl(C₁ -C₄)alkyl,hydrazinocarbonyl(C₁ -C₄)alkyl, aminocarbonyl(C₁ -C₄)alkyl substitutedwith phenyl which may have 1 to 3 suitable substituent(s), cyano(C₁-C₄)alkylaminocarbonyl(C₁ -C₄)alkyl, phenylsulfonylaminocarbonyl(C₁-C₄)alkyl, (C₁ -C₄)alkoxycarbonyl(C₁ -C₄)alkylaminocarbonyl(C₁-C₄)alkyl, and the most preferred one may be carboxymethyl,carboxyethyl, methoxycarbonylethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, benzoylmethyl, carbamoylmethyl, acetylmethyl,t-butoxycarbonylmethyl, morpholinocarbonylmethyl, pyridylcarbonylmethyl,chlorothienylcarbonylmethyl, pyrrolinylcarbonylmethyl,acetylpiperazinylcarbonylmethyl, phenylpiperazinylcarbonylmethyl,methylpiperazinylcarbonylmethyl, dimethylaminocarbonylmethyl,dimethylaminocarbonylethyl, trifluoromethylmethylaminocarbonylmethyl,cyanomethylaminocarbonylmethyl, cyclopentylaminocarbonylmethyl,methoxyethylaminocarbonylmethyl, dimethoxyethylaminocarbonylmethyl,dimethoxyphosphorylmethyl, diethoxyphosphorylmethyl,hydroxyethylaminocarbonylmethyl, dihydroxyethylaminocarbonylmethyl,trifluoromethylthiadiazolylaminocarbonylmethyl,thiazolylaminocarbonylmethyl, pyridylaminocarbonylmethyl,morpholinoaminocarbonylmethyl, pyridyl-N-methylaminocarbonylmethyl,methyloxadiazolylaminocarbonylmethyl, pyridylmethylaminocarbonylmethyl,tetrahydrofuranylmethylaminocarbonylmethyl, hydrazinocarbonylmethyl,dimethylaminophenylaminocarbonylmethyl,trifluoromethylphenylaminocarbonylmethyl,cyanomethylaminocarbonylmethyl, phenylsulfonylaminocarbonylmethyl orethoxycarbonylmethylaminocarbonylmethyl.

The preferred examples of "mono-(or di- or tri-)-halo(lower)alkyl" maybe fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl,tribromomethyl, 1-(or 2-)fluoroethyl, 1-(or 2-)bromoethyl, 1-(or2-)chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, or the like, inwhich the preferred one may be mono-(or di- or tri-)halo(C₁ -C₄)alkyl,and the most preferred one may be difluoromethyl or trifluoromethyl.

The preferred examples of "lower alkylthio" may be methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, or the like, inwhich the preferred one may be (C₁ -C₄)alkylthio, and the most preferredone may be methylthio.

The preferred examples of "cyclo(lower)alkyl(lower)alkyl" may becyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,cyclohexylethyl, or the like, in which the preferred one may be cyclo(C₃-C₆)alkyl(C₁ -C₄)alkyl, and the most preferred one may becyclohexylmethyl.

Suitable "acylamino" moiety in the term of "acylamino-(lower) alkyl" canbe referred to aforementioned "acylamino".

The preferred examples of "acylamino(lower)alkyl" may be loweralkoxycarbonylamino(lower)alkyl, lower alkanoylamino(lower)alkyl,heterocyclic-carbonylamino-(lower)alkyl, ##STR11## (wherein A⁴ and A⁵are each lower alkylene, amino(lower)alkylene or aminophenylene, and

R¹¹ is lower alkyl or hydrogen),

in which the preferred one may be (C₁ -C₄)alkoxycarbonylamino-(C₁-C₄)alkyl, (C₁ -C₄)alkanoylamino(C₁ -C₄)alkyl, carbonylamino(C₁-C₄)alkyl substituted with saturated 3 to 8-membered heteromonocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),##STR12## (wherein A⁴ and A⁵ are each (C₁ -C₆)alkylene, amino(C₁-C₆)-alkylene or aminophenylene, and

R¹¹ is (C₁ -C₆)alkyl or hydrogen),

and the most preferred one may be t-butoxycarbonyl aminomethyl,acetylaminomethyl or morpholinocarbonylaminomethyl.

Suitable "acyl" moiety in the terms of "acyl(lower)-alkenyl" can bereferred to aforementioned "acyl" moiety.

Suitable "(lower)alkenyl" moiety in the term of "acyl(lower)alkenyl" canbe referred to aforementioned "lower alkenyl".

The preferred examples of "acyl(lower)alkenyl" may be protectedcarboxy(lower)alkenyl, in which the preferred one may be (C₁-C₄)alkoxycarbonyl(C₁ -C₄)alkenyl, and the most preferred one may beethoxycarbonylvinyl.

Suitable "acyl" moiety in the term of "acyloxy(lower)alkyl" can bereferred to aforementioned "acyl" moiety.

The preferred examples of "acyloxy(lower)alkyl" may be loweralkanoyloxy(lower)alkyl, cyclo(lower)alkylcarbonyloxy(lower)alkyl,protected carboxyoxy(lower)alkyl, aroyloxy(lower)alkyl, or lower alkylsubstituted with ##STR13## (wherein A⁴ is lower alkylene,amino(lower)alkylene or aminophenylene, and

R¹¹ is lower alkyl or hydrogen),

in which the preferred one may be (C₁ -C₄)-alkanoyloxy (C₁ -C₄)alkyl,cyclo(C₃ -C₆)-alkylcarbamoyloxy (C₁ -C₄)alkyl, (C₁-C₄)-alkoxycarbonyloxy (C₁ -C₄)alkyl, benzoyloxy-(C₁ -C₄)alkyl, or loweralkyl substituted with ##STR14## (wherein A⁴ is (C₁ -C₆)alkylene,amino(C₁ -C₆)alkylene or aminophenylene, and

R¹¹ is (C₁ -C₆)alkyl or hydrogen),

and the most preferred one may be acetyloxymethyl, 1-acetyloxyethyl,cyclohexylcarbonyloxymethyl, ethoxycarbonyloxymethyl orbenzoyloxymethyl.

Suitable "acyl" moiety in the term of "acyl(lower)alkylthio(lower)alkyl"can be referred to aforementioned "acyl" moiety.

The preferred examples of "acyl(lower)alkylthio(lower)alkyl" may beprotected carboxy(lower)alkylthio(lower)alkyl, in which the preferredone may be (C₁ -C₄)alkoxycarbonyl(C₁ -C₄)alkylthio(C₁ -C₄)alkyl, and themost preferred one may be ethoxycarbonylmethylthiomethyl.

The preferred examples of "amino(lower)alkyl" may be amino(C₁ -C₄)alkyl,in which the most preferred one may be aminomethyl.

The preferred examples of "mono-(or di-)lower alkylamino" may bemethylamino, dimethylamino, ethylamino, diethylamino, propylamino,dipropylamino, butylamino, dibutylamino, pentylamino, dipentylamino,hexylamino, dihexylamino, or the like, in which the preferred one may bemono-(or di-)(C₁ -C₄)alkylamino, and the most preferred one may bemethylamino, dimethylamino or diethylamino.

The preferred examples of "lower alkylthio(lower)alkyl" may bemethylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl,ethylthiomethyl, ethylthioethyl, ethylthiopropyl, propylthiomethyl,propylthioethyl, propylthiopropyl, or the like, in which the preferredone may be (C₁ -C₄)alkylthio(C₁ -C₄)alkyl, and the most preferred onemay be methylthiomethyl.

The preferred examples of "hydroxyimino(lower)alkyl which may have oneor more suitable substituent(s)" may be hydroxyiminomethyl,1-hydroxyiminoethyl, hydroxyimino-1-methylethyl,hydroxyimino-1-methylpropyl, hydroxyimino-1-methylpropyl,hydroxyimino-1-amino-methyl, 2-hydroxyimino-2-amino-ethyl,hydroxyimino-1-aminopropyl, or the like, in which the preferred one maybe hydroxyimino(C₁ -C₄)alkyl which may have amino, and the mostpreferred one may be 1-hydroxyiminoethyl or 2-hydroxyimino-2-aminoethyl.

The preferred examples of "hydroxy(lower)alkylthio(lower)alkyl" may behydroxymethylthiomethyl, 2-hydroxymethylthioethyl,2-hydroxymethylthiopropyl, 4-hydroxymethylthiobutyl,5-hydroxymethylthiopentyl, hydroxymethylthiohexyl,(2-hydroxyethyl)thiomethyl, 2-(1-hydroxyethyl)thioethyl, (1- or2-hydroxyethyl)thiopropyl, (1- or 2-hydroxyethyl)-thiobutyl, (1- or2-hydroxyethyl)thiopentyl, (1- or 2-hydroxyethyl)thiohexyl, or the like,in which the preferred one may be hydroxy(C₁ -C₄)alkylthio(C₁ -C₄)alkyl,and the most preferred one may be (2-hydroxyethyl)thiomethyl.

The preferred examples of "cyano(lower)alkyl" may be cyanomethyl, 1-(or2-)cyanoethyl, 1-(or 2- or 3-)cyanopropyl, 1-(or 2- or 3- or4-)cyanobutyl, 1-(or 2- or 3- or 4- or 5-)cyanopentyl, 1-(or 2- or 3- or4- or 5- or 6-)cyanohexyl, or the like, in which the preferred one maybe cyano(C₁ -C₄)-alkyl, and the most preferred one may be cyanomethyl or2-cyanoethyl.

Suitable "mono-(or di-)lower alkoxy(lower)alkyl" may be methoxymethyl,methoxyethyl, dimethoxymethyl, dimethoxyethyl, ethoxymethyl,ethoxyethyl, diethoxymethyl, diethoxyethyl, propoxymethyl, propoxyethyl,propoxypropyl, dipropoxymethyl, dipropoxyethyl, dipropoxypropyl, or thelike, in which the preferred one may be mono-(or di-)(C₁ -C₄)alkoxy(C₁-C₄)alkyl, and the most preferred one may be methoxymethyl,2-methoxyethyl or 3-diethoxypropyl.

The preferred examples of "mono-(or di-)lower alkoxy(lower)alkyl whichmay have one or more suitable substituent(s)" may be (C₁ -C₄)alkoxy(C₁-C₄)alkyl or tri-halo(C₁ -C₄)alkyl(C₁ -C₄)alkoxy(C₁ -C₄)alkyl, and themost preferred one may be methoxymethyl, 2-methoxyethyl,3-diethoxypropyl or trifluoromethylmethoxymethyl.

Suitable "lower alkyl substituted with aryl" may be benzyl, phenethyl,2-phenylpropyl, naphthylmethyl, naphthylethyl, anthrylmethyl,1-anthrylethyl, or the like, in which the more preferred one may bephenyl(C₁ -C₄)alkyl, naphthyl(C₁ -C₄)alkyl or anthryl(C₁ -C₄)alkyl, andthe most preferred one may be benzyl.

The preferred examples of "lower alkyl substituted with aryl which mayhave one or more suitable substituent(s)" may be the one which may have1 to 3 nitro or cyano, such as phenyl(C₁ -C₄)alkyl, nitrophenyl(C₁-C₄)alkyl or cyanophenyl(C₁ -C₄)alkyl, in which the most preferred onemay be benzyl, 4-nitrobenzyl or 3-cyanobenzyl.

The preferred examples of "mono-(or di-)lower alkylamino(lower)alkyl"may be mono-(or di-)(C₁ -C₄)alkylamino(C₁ -C₄)alkyl, in which the morepreferred one may be dimethylaminomethyl.

Suitable "heterocyclic group" moiety in the term of "lower alkylsubstituted with heterocyclic group which may have one or more suitablesubstituent(s)" can be referred to aforementioned "heterocyclic group".

The preferred examples of "lower alkyl substituted with heteocyclicgroup which may have one or more suitable substituent(s)" may beimidazolyl(lower)alkyl, pyridyl(lower)alkyl, morpholino(lower)alkyl,pyrrolidinyl(lower)alkyl, tetrazolyl(lower)alkyl, oxiranyl(lower)alkyl,lower alkyl substituted with methylenedioxyphenyl having halogen, loweralkyl substituted with piperazine having (lower)alkyl, lower alkylsubstituted with oxadiazole having (lower)alkyl, in which the morepreferred one may be imidazolyl(C₁ -C₄)alkyl, pyridyl(C₁ -C₄)-alkyl,morpholino(C₁ -C₄)alkyl, pyrrolidinyl(C₁ -C₄)alkyl, tetrazolyl(C₁-C₄)alkyl, oxiranyl(C₁ -C₄)alkyl, (C₁ -C₄)alkyl substituted withmethylenedioxyphenyl having halogen, (C₁ -C₄)alkyl substituted withpiperazine having (C₁ -C₄)alkyl, (C₁ -C₄)alkyl substituted withoxadiazole having (C₁ -C₆)-alkyl, and the most preferred one may beimidazolylmethyl, pyridylmethyl, 3-pyridylpropyl, morpholinomethyl,2-morpholinoethyl, 2-pyrrolidinylethyl, tetrazolylmethyl,oxiranylmethyl, chloromethylenedioxyphenylmethyl,N-methylpiperazinylpropyl, 5-methyloxadiazolylmethyl.

Suitable "heterocyclic group" moiety in the term of "heterocyclic groupwhich may have one or more suitable substituent(s)" can be referred toaforementioned "heterocyclic group".

The preferred examples of "heterocyclic group which may have one or moresuitable substituent(s)", may be pyridyl which may have 1 to 3substituent(s) selected from the group consisting of halogen and loweralkyl, thiazolyl which may have 1 to 3 lower alkanoylamino, benzothienylwhich may have 1 to 3 halogen, indolyl which may have 1 to 3substituent(s) selected from the group consisting of halogen and loweralkyl, oxazolyl which may have 1 to 3 lower alkyl, pyranyl which mayhave 1 to 3 substituent(s) selected from the group consisting of loweralkyl and oxo, pyrrolyl which may have 1 to 3 lower alkyl, phthalimidowhich may have nitro, phthalimidine which may have nitro, piperidylwhich may have 1 to 3 lower alkyl.

Suitable "heterocyclic" moiety in the term of"heterocyclicthio(lower)alkyl" can be referred to aforementioned to"heterocyclic group".

The preferred examples of "heterocyclicthio(lower)alkyl" may beimidazolylthio(lower)alkyl, pyridylthio(lower)alkyl orbenzimidazolylthio(lower)alkyl, in which the preferred one may beimidazolylthio(C₁ -C₄)alkyl or benzimidazolyl(C₁ -C₄)-alkyl, and themost preferred one may be imidazolylthiomethyl or benzimidazolylmethyl.

Suitable "heterocyclic" moiety in the term of "heterocyclicthio" can bereferred to aforementioned "heterocyclic group".

The preferred examples of "heterocyclicthio" may be pyridylthio.

Suitable "heterocyclic" moiety in the term of "heterocyclic oxy" can bereferred to aforementioned "heterocyclic group".

The preferred examples of "heterocyclic oxy" may be pyridyloxy.

Suitable "heterocyclic" moiety in the term of "heterocyclicoxy(lower)alkyl" can be referred to aforementioned "heterocyclic group".

The preferred examples of "heterocyclic oxy(lower)alkyl" may bepyridyloxy(lower)alkyl, in which the more preferred one may bepyridyloxy(C₁ -C₄)alkyl, and the most preferred one may bepyridyloxymethyl.

Suitable "heterocyclic" moiety in the term of "heterocyclicaminoimino(lower)alkyl" can be referred to aforementioned "heterocyclicgroup".

The preferred examples of "heterocyclic aminoimino(lower)alkyl" may beaminoimino(lower)alkyl substituted with unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), in which themore preferred one may be pyridylaminoimino(C₁ -C₄)alkyl, and the mostpreferred one may be 2-pyridylaminoiminopropyl.

The preferred examples of "suitable substituent(s)" in the terms of"lower alkylene which may have one or more suitable substituent(s)" and"lower alkenylene which may have one or more suitable substituent(s)"may be lower alkyl, hydroxy, oxo, or the like, in which the preferredone may be (C₁ -C₄)alkyl, hydroxy or oxo, and the most preferred one maybe methyl, hydroxy or oxo.

The preferred examples of "suitable substituent(s)" in the terms of"aryl which may have one or more suitable substituent(s)" may behalogen, lower alkyl, nitro, lower alkoxy, an acyl group,cyclo(lower)alkyl, mono-(or di- or tri-)halo(lower)alkyl, acylamino,aryl, amino, mono-(or di-)lower alkylamino, aryloxy, acyl(lower)alkyl,hydroxy, hydroxy(lower)alkyl which may have one or more suitablesubstituent(s), heterocyclic group which may have one or more suitablesubstituent(s), mono-(or di-)lower alkylamino(lower)alkyl oracyl(lower)alkyl.

The preferred examples of "mono-(or di-)lower alkylamino(lower)alkyl"may be mono-(or di-)(C₁ -C₄)alkylamino(C₁ -C₄)alkyl, in which thepreferred one may be di(C₁ -C₄)alkylamino(C₁ -C₄)alkyl, and the mostpreferred one may be dimethylaminomethyl.

Suitable "acyl" moiety in the term of "acyl(lower)alkoxy" can bereferred to aforementioned "acyl" moiety.

The preferred examples of "acyl(lower)alkoxy" may be protectedcarboxy(lower)alkoxy, in which the more preferred one may be (C₁-C₄)alkoxycarbonyl(C₁ -C₄)alkoxy, and the most preferred one may beethoxycarbonylmethoxy.

The preferred examples of "suitable substituent(s)" in the term of"naphthyl which may have one or more suitable substituent(s)" may belower alkoxy, in which the more preferred one may be (C₁ -C₄)alkoxy, andthe most preferred one may be methoxy.

Suitable "acyl" moiety in the term of "acyl(lower)alkenyl" can bereferred to aforementioned "acyl" moiety.

Suitable "(lower)alkenyl" moiety in the term of "acyl(lower)alkenyl" canbe referred to aforementioned "lower alkenyl".

The preferred examples of "acyl(lower)alkenyl" may be protectedcarboxy(C₂ -C₆)alkenyl, in which the more preferred one may be loweralkoxycarbonyl(C₂ -C₄)alkenyl, and the most preferred one may beethoxycarbonylvinyl.

The preferred examples of "aryloxy" may be phenoxy, naphthyloxy,anthryloxy, or the like, in which the most preferred one may be phenoxy.

The preferred examples of "aryl(lower)alkoxy" may be phenyl(C₁-C₆)alkoxy, naphthyl(C₁ -C₆)alkoxy, anthryl(C₁ -C₆)-alkoxy, or the like,in which the preferred one may be phenyl(C₁ -C₄)alkoxy, and the mostpreferred one may be phenylmethoxy.

The processes for preparing the object compound (I) of the presentinvention are explained in detail in the following.

Process 1

The compound (Ia) or a salt thereof can be prepared by reacting thecompound (II) or its reactive derivative at the amino group or a saltthereof with the compound (III) or its reactive derivative at thecarboxy group or sulfo group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (II) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (II) with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound (II) with a silyl compound such asN,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like;a derivative formed by the reaction of the compound (II) with phosphorustrichloride or phosgene, and the like.

Suitable reactive derivative of the compound (III) may include an acidhalide, an acid anhydride, an activated ester, and the like. Thesuitable example may be an acid chloride; acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid (e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorus acid, sulfurous acid, thiosulfuric acid,alkanesulfuric acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g. cyanomethyl ester, methoxymethylester, dimethyliminomethyl (CH₃)₂ ⁺ N═CH--! ester, vinyl ester,propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with aN-hydroxy compound (e.g., N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole,N-hydroxyphthalimide, 1-hydroxy-6-chloro-lH-benzotriazole, etc.); andthe like. These reactive derivatives can optionally be selected fromthem according to the kind of the compound (III) to be used.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, dioxane, diethyl ether or any other solvents which do notadversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal (e.g., sodium, potassium, etc.),an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,etc.), an alkali metal hydrogencarbonate (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate, etc.),tri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), alkali metal hydride (e.g., sodiumhydride, etc.), alkali metal (lower)alkoxide (e.g., sodium methoxide,sodium ethoxide, etc.), pyridine, lutidine, picoline,dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

Process 2

The compound (Ib) or a salt thereof can be prepared by reacting thecompound (IV) or its reactive derivative at the carboxy group or a saltthereof with the compound (V) or its reactive derivative at the aminogroup or a salt thereof.

This reaction can be carried out in a similar manner to that of theaforementioned Process 1, and therefore the reagents to be used and thereaction conditions (e.g., solvent, reaction temperature, etc.) can bereferred to those of the Process 1.

Process 3

The compound (Ic) or a salt thereof can be prepared by reacting thecompound (VI) or its reactive derivative at the hydroxy group or a saltthereof with the compound (VII) or a salt thereof.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, dioxane, diethyl ether or any other solvents which do notadversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The reaction is usually carried out in the presence of an acid includingLewis acid.

Suitable acid may include an organic acid e.g. formic acid, acetic acid,propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.! and aninorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid,hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride,zinc bromide, etc.), etc.! and the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal (e.g., sodium, potassium, etc.),an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,etc.), an alkali metal hydrogencarbonate (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate, etc.),tri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), alkali metal hydride (e.g., sodiumhydride, etc.), alkali metal (lower)alkoxide (e.g. sodium methoxide,sodium ethoxide, etc.), pyridine, lutidine, picoline,dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

When the base, the acid and/or the starting compound are in liquid, theycan be used also as a solvent.

Process 4

The compound (Id) or a salt thereof can be prepared by reacting thecompound (VIII) or a salt thereof with the compound (IX) or a saltthereof to Wittig Reaction.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,dimethylsulfoxide, nitromethane, tetrahydrofuran, toluene, methylenechloride, ethylene-dichloride, chloroform, dioxane, diethyl ether or anyother solvents which do not adversely affect the reaction, or themixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal (e.g., sodium, potassium, etc.),an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,etc.), an alkali metal hydrogencarbonate (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate, etc.),tri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), alkali metal hydride (e.g., sodiumhydride, etc.), alkali metal (lower)alkoxide (e.g. sodium methoxide,sodium ethoxide, potassium t-butoxide, etc.), pyridine, lutidine,picoline, dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline, methyllitium,n-butyllitium, phenyllitium, 1,5-diazabicyclo 4.3.0!non-5-ene, or thelike.

When the base, the acid and/or the starting compound are in liquid, theycan be used also as a solvent.

Process 5

The compound (Ie) or a salt thereof can be prepared by reacting thecompound (X) or its reactive derivative at the amino group or a saltthereof with the compound (XI) or a salt thereof.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, dioxane, diethyl ether or any other solvents which do notadversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The reaction is usually carried out in the presence of an acid includingLewis acid.

Suitable acid may include an organic acid e.g. formic acid, acetic acid,propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.! and aninorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid,hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride,zinc bromide, etc.), etc.! and the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal (e.g., sodium, potassium, etc.),an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,etc.), an alkali metal hydrogencarbonate (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate, etc.),tri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), alkali metal hydride (e.g., sodiumhydride, etc.), alkali metal (lower)alkoxide (e.g., sodium methoxide,sodium ethoxide, etc.), pyridine, lutidine, picoline,dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

When the base, the acid and/or the starting compound are in liquid, theycan be used also as a solvent.

Process 6

The compound (If) or a salt thereof can be prepared by reacting thecompound (VI) or its reactive derivative at the hydroxy group or a saltthereof with the compound (XII) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the hydroxy group of the compound (VI)may include halide, sulfonate, sulfate, diazo compound, and the like.

Suitable reactive derivative at the carboxy group of the compound (XII)may include an acid halide, an acid anhydride, an activated ester, andthe like. The suitable example may be an acid chloride; acid azide; amixed acid anhydride with an acid such as substituted phosphoric acid(e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoricacid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorus acid, sulfurous acid, thiosulfuric acid,alkanesulfuric acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethylester, dimethyliminomethyl (CH₃)₂ ⁺ N═CH--! ester, vinyl ester,propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with aN-hydroxy compound (e.g., N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole,N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); andthe like. These reaction derivatives can optionally be selected fromthem according to the kind of the compound (XII) to be used.

This reaction is usually carried out in the presence of a base.

Suitable base may include, for example, an inorganic base such as alkalimetal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),alkaline earth metal hydroxide (e.g., magnesium hydroxide, calciumhydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate,potassium carbonate, cesium carbonate, etc.), alkaline earth metalcarbonate (e.g., magnesium carbonate, calcium carbonate, etc.), alkalimetal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate,etc.), alkali metal acetate (e.g., sodium acetate, potassium acetate,etc.), alkaline earth metal phosphate (e.g., magnesium phosphate,calcium phosphate, etc.), alkali metal hydrogen phosphate, (e.g.,disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.) orthe like, and an organic base such as trialkylamine (e.g.,trimethylamine, triethylamine, etc.), pyridine, picoline,N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo4.3.0!non-5-ene, 1,4-diazabicyclo 2.2.2!-octane, 1,5-diazabicyclo5.4.0!undecene-5 or the like.

This reaction is usually carried out in a solvent such as benzene,N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride,ethylene dichloride, chloroform or any other solvents which do notadversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Process 7

The object compound (Ih) or a salt thereof can be prepared by reacting acompound (Ig) or its reactive derivative at the carboxy group or a saltthereof with a compound (XIII) or its reactive derivative at the aminogroup or a salt thereof.

Suitable reactive derivative at the carboxy group of the compound (Ig)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.!,dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid e.g., methanesulfonic acid, etc.!, aliphaticcarboxylic acid e.g., acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.! or aromatic carboxylicacid e.g., benzoic acid, etc.!; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; oran activated ester e.g. cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl (CH₃)₂ ⁼ N═CH--! ester, vinyl ester, propargylester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.!, or an ester with a N-hydroxy compound e.g.,N,N-dimethylhydroxyamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-lH-benzotriazole,etc.!, and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (Ig) to beused.

Suitable salts of the compound (Ig) and its reactive derivative can bereferred to the ones as exemplified for the compound (I).

Suitable reactive derivative at the amino group of the compound (XIII)may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (XIII) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (XIII) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofthe compound (XIII) with phosphorus trichloride or phosgene, and thelike.

Suitable salts of the compound (XIII) and its reactive derivative can bereferred to the ones as exemplified for the compound (I).

The reaction is usually carried out in a conventional solvent such aswater, alcohol e.g., methanol, ethanol, etc.!, acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (Ig) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N'-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkylphosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkylhaloformate e.g. ethyl chloroformate, isopropyl chloroformate, etc.!;triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-S-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, methanesulfonyl chloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal carbonate, alkali metalbicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

Process 8

The compound (Ij) or a salt thereof can be prepared by reacting thecompound (Ii) or a salt thereof with Grignard Reagent.

Suitable Grignard reagent to be used in the present reaction may includethe compound of the formula:

    R.sup.12 --MgX"                                            (XIV)

(wherein R¹² is lower alkyl, and X" is halogen.)

This reaction is usually carried out in a solvent such astetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, dioxane, diethyl ether or any other solvent which do notadversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Process 9

The object compound (Il) or a salt thereof can be prepared by subjectinga compound (Ik) or a salt thereof to de-acylation reaction of acylaminogroup.

This reaction is carried out in accordance with a conventional methodsuch as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid. Suitable base may include an inorganic baseand an organic base such as an alkali metal e.g., sodium, potassium,etc.!, an alkaline earth metal e.g., magnesium, calcium, etc.!,thehydroxide or carbonate or bicarbonate thereof, trialkylamine e.g.,trimethylamine, triethylamine, etc.!, picoline, 1,5-diazabicyclo4.3.0!non-5-ene, 1,4-diazabicyclo 2.2.2!-octane, 1,8-diazabicyclo5.4.0!undec-7-ene, or the like.

Suitable acid may include an organic acid e.g., formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.!and an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogen chloride, hydrogen bromide, etc.!.

The elimination using Lewis acid such as trihaloacetic acid e.g.trichloroacetic acid, trifluoroacetic acid, etc.! or the like ispreferably carried out in the presence of cation trapping agents e.g.anisole, phenol, etc.!.

The reaction is usually carried out in a solvent such as water, analcohol e.g. methanol, ethanol, etc.!, methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical and thereaction is usually carried out under cooling to warming.

The reduction method applicable for the elimination reaction may includechemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal e.g., tin, zing, iron, etc.! or metallic compounde.g., chromium chloride, chromium acetate, etc.! and an organic orinorganic acid e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.!.

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.!, palladium catalysts e.g., spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium, sulfate, palladium on barium carbonate, etc.!, nickel catalystse.g., reduced nickel, nickel oxide, Raney nickel, etc.!, cobaltcatalysts e.g. reduced cobalt, Raney cobalt, etc.!, iron catalysts e.g.reduced iron, Raney iron, etc.!, copper catalysts e.g. reduced copper,Raney copper, Ullman copper, etc.! and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

Process 10

The compound (Ik) or a salt thereof can be prepared by subjecting thecompound (Il) or its reactive derivative at the amino group, or a saltthereof to acylation reaction.

Suitable acylating agent to be used in the present acylation reactionmay include the compound of the formula:

    R.sup.13 --OH                                              (XV)

(wherein R¹³ is acyl) or its reactive derivative, or a salt thereof.

Suitable reactive derivative at the amino group of the compound (Il) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (Il) with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound (Il) with a silyl compound such as N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; aderivative formed by the reaction of the compound (Il) with phosphorustrichloride or phosgene, and the like.

Suitable reactive derivative of the compound (XV) may include an acidhalide, an acid anhydride, an activated ester, and the like. Thesuitable example may be an acid chloride; acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid (e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g., cyanomethyl, ester methoxymethylester, dimethyliminomethyl (CH₃)₂ ⁺ N═CH--! ester, vinyl ester,propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenylthioester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with aN-hydroxy compound (e.g., N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole,N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); andthe like. These reactive derivatives can optionally be selected fromthem according to the kind of the compound (XV) to be used.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which donot adversely affect the reaction, or the mixture thereof.

When the compound (XV) is used in free acid form or its salt form in thereaction, the reaction is preferably carried out in the presence of aconventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide);N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonyl-bis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine, ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate;phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride;thionyl chloride; oxalyl chloride; triphenylphosphite;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an organic orinorganic base such as an alkali metal bicarbonate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine,N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to heating.

Process 11

The compound (Im) or a salt thereof can be prepared by subjecting thecompound (Ij) or a salt thereof to acylation reaction. This reaction canbe carried out in a similar manner to that of the afore-mentionedProcess 10, and therefore the reagents to be used and the reactionconditions (e.g., solvent, reaction temperature, etc.) can be referredto those of the Process 10.

In the starting compound (II), the compound (IIa) can be preparedaccording to the following reaction scheme. ##STR15## wherein R¹, R²,R³, ---and X are each as defined above.

The reaction of this process can be carried out according to the methodof Preparation 42 (1) mentioned below is or the similar manners thereto.

Among the starting compounds (II) to (XVI), some of them are novelcompounds. They can be prepared by the similar manners to thosedisclosed in Preparations mentioned later in the present specification,or any process known in this field of the art for preparing structurallyanalogous compounds thereto.

The compounds obtained by the above Processes 1 to 11 can be isolatedand purified by a conventional method such as pulverization,recrystallization, columnchlomatography, reprecipitation or the like.

It is to be noted that each of the object compound (I) may include oneor more stereoisomer such as optical isomer(s) and geometrical isomer(s)due to asymmetric carbon atom(s) and double bond(s) and all such isomersand mixture thereof are included within the scope of this invention.

The pharmaceutical composition of the present invention can be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains the object compound (I) or apharmaceutically acceptable salt thereof, as an active ingredient inadmixture with an organic or inorganic carrier or excipient which issuitable for rectal; pulmonary (nasal or buccal inhalation); ocular;external (topical); oral administration; parenteral (includingsubcutaneous, intravenous and intramuscular) administrations;insufflation (including aerosols from metered dose inhalator);nebulizer; or dry powder inhalator.

The active ingredient may be compounded, for example, with the usualnon-toxic, pharmaceutically acceptable carriers in a solid form such asgranules, tablets, dragees, pellets, troches, capsules, orsuppositories; creams; ointments; aerosols; powders for insufflation; ina liquid form such as solutions, emulsions, or suspensions forinjection; ingestion; eye drops; and any other form suitable for use.And, if necessary, there may be included in the above preparationauxiliary substance such as stabilizing, thickening, wetting,emulsifying and coloring agents; perfumes or buffer; or any othercommonly may be used as additives.

The object compound (I) or a pharmaceutically acceptable salt thereofinclude solvated compound e.g., enclosure compound (e.g., hydrate,etc.)!.

The object compound (I) or a pharmaceutically acceptable salt thereofinclude both its crystal form and non-crystal form.

The object compound (I) or a pharmaceutically acceptable salt thereofis/are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or conditionof diseases.

The pharmaceutical composition of the present invention can bemanufactured by the conventional method in this field of the art. Ifnecessary, the technique generally used in this field of the art forimproving the bioavailability of a drug can be applied to thepharmaceutical composition of the present invention.

While the dosage of therapeutically effective amount of the objectcompound (I) varies from and also depends upon the age and condition ofeach individual patient to be treated, in the case of intravenousadministration, a daily dose of 0.001-100 mg of the object compound (I)per kg weight of a human being or an animal, in the case ofintramuscular administration, a daily dose of 0.001-100 mg of the objectcompound (I) per kg weight of a human being of an animal, in case oforal administration, a daily dose of 0.001-200 mg of the object compound(I) per kg weight of a human being or an animal is generally given forthe prevention and/or the treatment of aforesaid diseases 1 to 4 times aday in a human being or an animal.

In order to illustrate the usefulness of the object compound (I), thepharmacological test data of the representative compound of thecompounds (I) is shown in the following.

Test Compound (1) 7-(2,6-Dichlorobenzoylamino)-2,3-dimethylbenzo b!furan

Test (Bone organ culture)

Test Method

Calvariae from Wistar rats were excised and cultured in wells of 12-wellculture plates containing 2 ml of Dulbecco's modified minimum essentialmedium supplemented with 10% fetal bovine serum and 10⁻⁸ M humanparathyroid hormone fragment (1-34) PTH! in the presence of the testcompound. In control dishes, PTH was not added. Control and PTH controlwere exposed to an equivalent concentration of the vehicle. Six dayslater, the concentration of calcium in the medium was measured bymethylxylenol blue method and the percentage of inhibition ofPTH-induced bone resorption was calculated according to followingformula. ##EQU1## Test Result

    ______________________________________    Compound dose = 1 × 10.sup.-5 (M)    Test Compound  Inhibition (%)    ______________________________________    (1)            100    ______________________________________

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

Preparation 1 (1)

To a solution of pentan-3-one oxime (6.00 g) in dimethylformamide (30ml) was added sodium hydride (60% oil suspension, 2.37 g) under icecooling. After 15 minutes, to the above mixture was added dropwise1-fluoro-2-nitrobenzene (5.98 g) in dimethylformamide (30 ml). Themixture was stirred for 3 hours at ambient temperature and poured into amixture of ice and water. The separated oil was extracted with diethylether. The organic layer was washed with water, dried over sodiumsulfate and evaporated in vacuo to give pentan-3-oneO-(2-nitrophenyl)oxime (10.51 g) as a brown oil.

NMR (CDCl₃, δ): 1.12-1.30 (6H, m), 2.40 (2H, q, J=7 Hz), 2.58 (2H, q,J=7 Hz), 7.03 (1H, dt, J=1 and 8 Hz), 7.53 (1H, dt, J=1 and 8 Hz), 7.75(1H, dd, J=1 and 8 Hz), 7.95 (1H, dd, J=1 and 8 Hz)

The following compounds Preparations 1 (2) to (8)! were obtainedaccording to a similar manner to that of Preparation 1 (1).

Preparation 1 (2)

Butan-2-one O-(4-carboxy-2-nitrophenyl)oxime

mp: 172°-178° C.

Preparation 1 (3)

Acetone O-(4-fluoro-2-nitrophenyl)oxime

mp: 76°-77° C. NMR (CDCl₃, δ): 2.05 (3H, s), 2.15 (3H, s), 7.27 (1H, m),7.63-7.75 (2H, m)

Preparation 1 (4)

2,3,5,6-Tetrahydro-4H-thiopyran-4-one O-(2-nitrophenyl)oxime

mp: 71°-73° C. NMR (CDCl₃, δ): 2.68-2.75 (2H, m), 2.78-2.93 (4H, m),3.07-3.17 (2H, m), 7.08 (1H, dt, J=1 and 8 Hz), 7.54 (1H, dt, J=1 and 8Hz), 7.72 (1H, dd, J=1 and 8 Hz), 7.95 (1H, dd, J=1 and 8 Hz)

Preparation 1 (5)

Acetone O-(4-chloro-2-nitrophenyl)oxime

mp: 62°-65° C. NMR (CDCl₃, δ): 2.05 (3H, s), 2.15 (3H, s), 7.49 (1H, d,J=7 Hz), 7.71 (1H, d, J=7 Hz), 7.94 (1H, s)

Preparation 1 (6)

Ethyl 5-(2-nitrophenyl)oxyiminohexanoate oil

Preparation 1 (7)

Cycloheptanone O-(2-nitrophenyl)oxime

NMR (CDCl₃, δ): 1.55-1.68 (4H, m), 1.68-1.79 (4H, m), 2.52 (2H, t, J=6Hz), 2.82 (2H, t, J=6 Hz), 7.02 (1H, t, J=8 Hz), 7.52 (1H, t, J=8 Hz),7.73 (1H, d, J=8 Hz), 7.91 (1H, d, J=8 Hz)

Preparation 1 (8)

4-Ethoxycarbonylbutan-2-one O-(2-nitrophenyl)oxime

ESI Mass: 281 (M+H)⁺, 303 (M+Na)⁺

Preparation 2 (1)

A mixture of 2-bromophenol (5 g), potassium carbonate (5.99 g) and2-chlorocyclohexanone (4.22 g) in N,N-dimethylformamide was stirred at60° C. for 4 hours. The reaction mixture was poured into cold water andthe separated oil was extracted with diethyl ether. The extract waswashed with water, dried over sodium sulfate and concentrated in vacuo.The residue was crystallized from n-hexane to give2-(2-bromophenoxy)cyclohexanone (4.36 g).

mp: 72°-73° C. NMR (CDCl₃, δ): 1.74 (1H, m), 1.85-2.05 (2H, m),2.10-2.40 (4H, m), 2.70 (1H, m), 4.64 (1H, dd, J=5 and 7.5 Hz), 6.81(1H, d, J=7.5 Hz), 6.85 (1H, t, J=7.5 Hz), 7.20 (1H, t, J=7.5 Hz), 7.54(1H, d, J=7.5 Hz)

The following compounds Preparations 2 (2) and (3)! were obtainedaccording to a similar manner to that of Preparation 2 (1).

Preparation 2 (2)

3-(2-Acetylamino-4-nitrophenoxy)-2-butanone NMR (CDCl₃, δ): 1.70 (3H, d,J=6 Hz), 2.22 (3H, s), 2.30 (3H, s), 4.87 (1H, q, J=6 Hz), 6.78 (1H, d,J=8 Hz), 7.91 (1H, dd, J=2 and 8 Hz), 8.19 (1H, br s), 9.30 (1H, d, J=2Hz)

Preparation 2 (3)

2',6'-Dichloro-5-methyl-2-(1-methyl-2-oxopropyl)-oxybenzophenone

mp: 111°-113° C. NMR (CDCl₃, δ): 0.97 (3H, d, J=7 Hz), 1.95 (3H, s),2.35 (3H, s), 4.42 (1H, q, J=7 Hz), 6.53 (1H, d, J=8 Hz), 7.20-7.35 (4H,m), 7.93 (1H, s)

Preparation 3

2,6-Dichlorobenzoyl chloride (2.14 g) was added to a solution ofp-cresol (1.08 g) and triethylamine (1.11 g) in dichloromethane (30 ml)dropwise at 4° C. The mixture was stirred at ambient temperatureovernight. The reaction mixture was washed with aqueous saturated sodiumbicarbonate and brine, dried over sodium sulfate and evaporated in vacuoto give 4-methylphenyl 2,6-dichlorobenzoate (2.73 g) as an oil. NMR(CDCl₃, δ): 2.38 (3H, s), 7.17 (2H, d, J=8 Hz), 7.25 (2H, d, J=7 Hz),7.30-7.45 (3H, m)

Preparation 4

A mixture of 4-methylphenyl 2,6-dichlorobenzoate (2.53 g) and aluminumchloride (2.4 g) in 1,2-dichloroethane (30 ml) was refluxed for 3 hours.The reaction mixture was cooled and poured into a mixture of ice and 1Nhydrochloric acid. The separated oil was extracted with dichloromethane.The extract was washed with brine, aqueous saturated sodium bicarbonateand brine, dried over sodium sulfate and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel and theobtained oil was crystallized from diethyl ether to give2',6'-dichloro-2-hydroxy-5-methylbenzophenone (1.72 g).

mp: 139°-141° C. NMR (CDCl₃, δ): 2.22 (3H, s), 6.90 (1H, s), 7.00 (1H,d, J=8 Hz), 7.30-7.45 (4H, m)

Preparation 5 (1)

To a suspension of butan-2-one O-(4-carboxy-2-nitrophenyl)oxime (4.5 g)in ethanol (45 ml) was added conc. sulfuric acid (6.8 ml) dropwise. Themixture was refluxed for 20 hours. The reaction mixture was cooled andpoured into a mixture of ice and water. The separated oil was extractedwith ethyl acetate. The extract was washed with brine, aqueous saturatedsodium bicarbonate and brine, dried over sodium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel. The first fractions were evaporated in vacuo and the residue wascrystallized from hexane to give 5-ethoxycarbonyl-2-ethyl-7-nitrobenzob!furan (0.82 g).

mp: 82°-83° C. NMR (CDCl₃, δ): 1.42 (3H, t, J=8 Hz), 1.46 (3H, t, J=8Hz), 2.95 (2H, q, J=8 Hz), 4.46 (2H, q, J=8 Hz), 6.61 (1H, s), 8.50 (1H,s), 8.75 (1H, s)

The second fractions were evaporated in vacuo and the residue wascrystallized from hexane to give2,3-dimethyl-5-ethoxycarbonyl-7-nitrobenzo b!furan (1.2 g).

mp: 123°-124° C. NMR (CDCl₃, δ): 1.45 (3H, t, J=8 Hz), 2.23 (3H, s),2.52 (3H, s), 4.47 (2H, q, J=8 Hz), 8.40 (1H, s), 8.73 (1H, s)

The following compounds Preparations 5 (2) to (7)! were obtainedaccording to a similar manner to that of Preparation 5 (1).

Preparation 5 (2)

5-Fluoro-2-methyl-7-nitrobenzo b!furan

mp: 103°-104° C. NMR (CDCl₃, δ): 2.58 (3H, s), 6.52 (1H, s), 7.48 (1H,d, J=8 Hz), 7.78 (1H, d, J=8 Hz)

Preparation 5 (3)

7-Acetylamino-2,3-dimethyl-5-nitrobenzo b!furan

mp: 197°-198.5° C. NMR (CDCl₃, δ): 2.20 (3H, s), 2.31 (3H, s), 2.45 (3H,s), 7.63 (1H, br s), 8.09 (1H, d, J=2 Hz), 9.02 (1H, m)

Preparation 5 (4)

6-Nitro-3,4-dihydro-1H-thiopyrano 4,3-b!benzofuran

mp: 114°-116° C. NMR (CDCl₃, δ): 3.03-3.12 (2H, m), 3.12-3.23 (2H, m),3.77-3.80 (2H, m), 7.35 (1H, t, J=8 Hz), 7.72 (1H, dd, J=1 and 8 Hz),8.10 (1H, dd, J=1 and 8 Hz)

Preparation 5 (5)

5-Chloro-2-methyl-7-nitrobenzo b!furan

mp: 153°-154° C. NMR (CDCl₃, δ): 2.58 (3H, s), 6.49 (1H, s), 7.73 (1H,s), 8.03 (1H, s)

Preparation 5 (6)

2-(3-Ethoxycarbonylpropyl)-7-nitrobenzo b!furan NMR (CDCl₃, δ): 1.27(3H, t, J=7 Hz), 2.13 (2H, quint., J=7 Hz), 2.44 (2H, t, J=7 Hz), 2.45(2H, t, J=7 Hz), 4.14 (2H, q, J=7 Hz), 6.57 (1H, s), 7.30 (1H, t, J=8Hz), 7.79 (1H, d, J=8 Hz), 8.07 (1H, d, J=8 Hz)

Preparation 5 (7)

1-Nitro-6,7,8,9-tetrahydro-5H-10-oxo-benzo b!azulene

mp: 74°-75° C. NMR (CDCl₃, δ): 1.77-1.92 (6H, m), 2.68-2.74 (2H, m),3.00-3.08 (2H, m), 7.29 (1H, t, J=8 Hz), 7.69 (1H, d, J=8 Hz), 8.01 (1H,d, J=8 Hz)

Preparation 6

A mixture of 2,4-bis(benzoylamino)phenol (6.0 g), 3-chlorobutan-2-one(2.3 g) and potassium carbonate (5.0 g) in N,N-dimethylformamide (30 ml)was stirred at 70° C. for 3 hours. The reaction mixture was cooled andpoured into water. The separated oil was extracted with ethyl acetate.The extract was washed with brine, dried over sodium sulfate andevaporated in vacuo. To the residue was added conc. sulfuric acid (30ml) and the mixture was stirred at 40° C. for 7 hours. The reactionmixture was cooled and poured into a mixture of ice and water. Theseparated oil was extracted with ethyl acetate and the extract waswashed with brine, dried over sodium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel and theobtained oil was crystallized from diethyl ether to give5,7-bis(benzoylamino)-2,3-dimethylbenzo b!furan (3.7 g).

mp: 185°-186° C. NMR (CDCl₃, δ): 2.16 (3H, s), 2.40 (3H, s), 7.40-7.65(6H, m), 7.85-8.00 (4H, m), 8.09 (2H, s), 8.15 (1H, s), 8.32 (1H, s)

Preparation 7

A mixture of pentan-3-one O-(2-nitrophenyl)oxime (10.50 g) in 10%hydrogen chloride-methanol (105 ml) was refluxed for 4 hours. Afterconcentration in vacuo, the residue was extracted with ethyl acetate andwater. The obtained organic layer was washed with saturated aqueoussodium bicarbonate, brine and dried over, sodium sulfate. Afterevaporation in vacuo, the residue was purified by column chromatographyon silica gel (eluate; ethyl acetate:n-hexane=1:6) to give a solid. Theresulting solid was triturated with a mixture of ethanol and water (2:1)and the precipitate was collected to give 2-ethyl-3-methyl-7-nitrobenzob!furan (4.44 g).

mp: 58°-60° C. NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 2.21 (3H, s), 2.87(2H, q, J=7 Hz) 7.29 (1H, t, J=8 Hz), 7.70 (1H, d, J=8 Hz), 8.03 (1H, d,J=8 Hz)

Preparation 8

A solution of 4-ethoxycarbonylbutan-2-one O-(2-nitrophenyl)oxime (7.83g) in 37% ethanolic hydrogen chloride (120 ml) was stirred at 80° C. for6 hours. The insoluble matter was filtered off and the filtrate wasevaporated in vacuo. The residue was purified by column chromatographyon silica gel and the obtained oil was crystallized from a mixture ofethanol (20 ml) and water (4 ml) to give a mixture of3-ethoxycarbonylmethyl-2-methyl-7-nitrobenzo b!furan and2-(2-ethoxycarbonylethyl)-7-nitrobenzo b!furan (3.41 g).

To a solution of these mixture (2.0 g) in dichloromethane was addedbromine (0.28 ml) in dichloromethane (1 ml) dropwise at 4° C. Themixture was stirred at 4° C. for 30 minutes and at ambient temperaturefor 1 hour. The reaction mixture was washed with 5% aqueous sodiumthiosulfate and aqueous saturated sodium bicarbonate, dried over sodiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel. The less polar fraction was combined andevaporated in vacuo to give3-bromo-2-(2-ethoxycarbonylethyl)-7-nitrobenzo b!furan (582 mg).

mp: 71°-74° C. NMR (CDCl₃, δ): 1.28 (3H, t, J=7 Hz), 2.84 (2H, t, J=7Hz), 3.27 (2H, t, J=7 Hz), 4.19 (2H, q, J=7 Hz), 7.41 (1H, t, J=8 Hz),7.79 (1H, d, J=8 Hz), 8.17 (1H, d, J=8 Hz)

The more polar fraction was combined and evaporated in vacuo. Theresidue was crystallized from a mixture of ethanol and water to give3-ethoxycarbonylmethyl-2-methyl-7-nitrobenzo b!furan (832 mg).

mp: 64°-68° C. NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 2.56 (3H, s), 3.63(2H, s), 4.17 (2H, q, J=7 Hz), 7.32 (1H, t, J=8 Hz), 7.80 (1H, d, J=8Hz), 8.07 (1H, d, J=8 Hz)

Preparation 9

A mixture of 2-methyl-7-nitrobenzo b!furan (2.66 g), N-bromosuccinimide(3.21 g) and 2,2'-azobis-(2,4-dimethyl-4-methoxyvaleronitrile) (270 mg)in dichloromethane (30 ml) was refluxed for 1 hour. The reaction mixturewas washed with aqueous saturated sodium bicarbonate and brine, driedover sodium sulfate and concentrated in vacuo. The residue wascrystallized from diethyl ether to give 2-bromomethyl-7-nitrobenzob!furan (3.3 g).

mp: 146°-147° C. NMR (CDCl₃, δ): 4.66 (2H, s), 6.92 (1H, s), 7.38 (1H,t, J=8 Hz), 7.87 (1H, d, J=8 Hz), 8.18 (1H, d, J=8 Hz)

Preparation 10

A mixture of 2-bromomethyl-7-nitrobenzo b!furan (512 mg), ethylmercaptoacetate (0.24 ml) and potassium carbonate (552 mg) inN,N-dimethylformamide (4 ml) was stirred at ambient temperature for 2hours. To the reaction mixture was added cold water and the separatedsolid was collected, washed with water and dried to give2-ethoxycarbonylmethylthiomethyl-7-nitrobenzo b!furan (546 mg).

mp: 84°-87° C. NMR (CDCl₃, δ): 1.30 (3H, t, J=8 Hz), 3.31 (2H, s), 4.08(2H, s), 4.20 (2H, q, J=8 Hz), 6.79 (1H, s), 7.34 (1H, t, J=8 Hz), 7.82(1H, d, J=8 Hz), 8.11 (1H, d, J=8 Hz)

Preparation 11 (1)

A solution of 2-(3-ethoxycarbonylpropyl)-7-nitrobenzo b!furan (1.0 g) ina mixture of aqueous 1N-sodium hydroxide (7.2 ml) and ethanol (5 ml) wasstirred at 50° C. for 1 hour. The reaction mixture was diluted withwater and acidified with 4N-hydrochloric acid. The separated solid wascollected, washed with water and dried to give2-(3-carboxypropyl)-7-nitrobenzo b!furan (752 mg).

mp: 180°-182° C. NMR (CDCl₃, δ): 2.11-2.21 (2H, m), 2.52 (2H, t, J=7Hz), 2.98 (2H, t, J=7 Hz), 6.59 (1H, s), 7.30 (1H, t, J=8 Hz), 7.80 (1H,d, J=8 Hz), 8.07 (1H, d, J=8 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 11 (1).

Preparation 11 (2)

2-Carboxymethylthiomethyl-7-nitrobenzo b!furan

mp: 92°-93° C. NMR (DMSO-d₆, δ): 3.37 (2H, s), 4.11 (2H, s), 7.02 (1H,s), 7.47 (1H, t, J=8 Hz), 8.06 (1H, d, J=8 Hz), 8.11 (1H, d, J=8 Hz)

Preparation 12 (1)

A solution of 2-(3-carboxypropyl)-7-nitrobenzo b!furan (500 mg) inthionyl chloride (5 ml) was refluxed for 1.5 hours. The reaction mixturewas diluted with toluene and concentrated in vacuo. The residue wasdissolved in dichloromethane (15 ml) and to the mixture was addedaluminum chloride (435 mg) at 4° C. The mixture was stirred at ambienttemperature for 2 hours and partitioned between 1N-hydrochloric acid anddichloromethane. The organic layer was separated, washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel and the obtained oil wascrystallized from a mixture of ethyl acetate and n-hexane to give6-nitro-1-oxo-1,2,3,4-tetrahydrodibenzofuran (282 mg).

mp: 122°-123.5° C. NMR (CDCl₃, δ): 2.30-2.41 (2H, m), 2.68 (2H, t, J=7Hz), 3.20 (2H, t, J=7 Hz), 7.49 (1H, t, J=8 Hz), 8.18 (1H, d, J=8 Hz),8.40 (1H, d, J=8 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 12 (1).

Preparation 12 (2)

1,2-Dihydro-6-nitro-1-oxo-4H-thiopyrano 3,4-b!benzo- b!furan

mp: 210°-211° C. NMR (CDCl₃, δ): 3.56 (2H, s), 4.13 (2H, s), 7.52 (1H,t, J=8 Hz), 8.20 (1H, d, J=8 Hz), 8.45 (1H, d, J=8 Hz)

Preparation 13

A mixture 1-hydroxyimino-6-nitro-1,2,3,4-tetrahydrodibenzofuran (425 mg)p-toluenesulfonyl chloride (394 mg) and triethylamine (521 mg) indichloromethane was stirred at ambient temperature for 2 hours. Themixture was directly purified by column chromatography on silica gel andthe obtained oil was crystallized from diisopropyl ether to give6-nitro-1,2,3,4-tetrahydro-1-p-toluenesulfonyloxyiminodibenzofuran (609mg).

mp: 175°-182° C. (dec.) NMR (CDCl₃, δ): 2.09-2.19 (2H, m), 2.46 (3H, s),2.65 (4/5H, m), 2.90 (6/5H, t, J=6 Hz), 2.98-3.11 (2H, m), 7.32-7.42(3H, m), 7.89-8.00 (2H, m), 8.07-8.19 (8/5H, m), 8.61 (2/5H, d, J=8 Hz)

Preparation 14

A mixture of 2-(2-boromophenoxy)cyclohexanone (4.306 g) andpolyphosphoric acid (40 g) was stirred at 50° C. for 4 hours. Thereaction mixture was poured into cold water and the separated oil wasextracted with ethyl acetate. The extract was washed with water, aqueoussaturated sodium bicarbonate and brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel. The appropriate fractions were combined and concentratedin vacuo to give 6-bromo-1,2,3,4-tetrahydrodibenzofuran (3.49 g) as anoil.

NMR (CDCl₃, δ): 1.85 (2H, m), 1.95 (2H, m), 2.61 (2H, m), 2.80 (2H, m),7.06 (1H, t, J=7.5 Hz), 7.33 (1H, d, J=7.5 Hz), 7.35 (1H, d, J=7.5 Hz)

Preparation 15

To a suspension of magnesium (345 mg) in tetrahydrofuran (5 ml) wasadded 6-bromo-1,2,3,4-tetrahydrodibenzofuran (3.39 g) in tetrahydrofuran(15 ml) dropwise. The mixture was refluxed for 1 hour and cooled to 4°C. Dry ice (2.7 g) was added to the mixture and the mixture was stirredat ambient temperature for 30 minutes. To the mixture was added 3.6%hydrochloric acid and chloroform. The organic layer was separated, driedover sodium sulfate and concentrated in vacuo. The residue wascrystallized from n-hexane to give1,2,3,4-tetrahydrodibenzofuran-6-carboxylic acid (2.60 g).

mp: 197°-198° C. NMR (CDCl₃, δ): 1.88 (2H, m), 1.97 (2H, m), 2.64 (2H,m), 2.85 (2H, m), 7.28 (1H, t, J=7.5 Hz), 7.65 (1H, d, J=7.5 Hz), 7.95(1H, d, J=7.5 Hz)

Preparation 16

A mixture of 7-carboxy-2,3-dimethylbenzo b!furan (2 g) andN,N-dimethylformamide (1 drop) in thionyl chloride (10 ml) was refluxedfor 2 hours. The reaction mixture was cooled and concentrated in vacuo.The crystalline residue was triturated with n-hexane to give7-chlorocarbonyl-2,3-dimethylbenzo b!furan (2.17 g).

mp: 75°-77° C. NMR (CDCl₃ δ): 2.19 (3H, s), 2.47 (3H, s), 7.32 (1H, t,J=7.5 Hz), 7.72 (1H, d, J=7.5 Hz), 8.03 (1H, d, J=7.5 Hz)

Preparation 17

Sodium borohydride (38 mg) was added to a solution of6-nitro-1-oxo-1,2,3,4-tetrahydrodibenzofuran (231 mg) in a mixture ofethanol (1.5 ml) and N,N-dimethylformamide (1.5 ml). The mixture wasstirred at ambient temperature for 20 minutes, diluted with water andacidified with 3.6% hydrochloric acid. The separated oil was extractedwith ethyl acetate and the extract was washed with aqueous saturatedsodium bicarbonate and brine, dried over sodium sulfate and concentratedin vacuo. The residue was crystallized from diisopropyl ether to give1-hydroxy-6-nitro-1,2,3,4-tetrahydrodibenzofuran (175 mg).

mp: 127°-129° C. NMR (CDCl₃, δ): 1.90-2.05 (2H, m), 2.05-2.20 (2H, m),2.88 (2H, m), 5.08 (1H, m), 7.35 (1H, t, J=7.5 Hz), 7.97 (1H, d, J=7.5Hz), 8.08 (1H, d, J=7.5 Hz)

Preparation 18 (1)

To a mixture of 2-methyl-7-nitrobenzo b!furan (177 mg) and aluminumchloride (200 mg) in dichloromethane (5 ml) was added dropwise propionylchloride (0.18 ml). The mixture was stirred at ambient temperature for 3hours and poured into a mixture of ice and 1N-hydrochloric acid. Theseparated oil was extracted with dichloromethane and the extract waswashed with brine, dried over sodium sulfate and evaporated in vacuo.The residue was crystallized from diethyl ether to give2-methyl-7-nitro-3-propionylbenzo b!furan (215 mg).

mp: 128°-129° C. NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.92 (3H, s),2.99 (2H, q, J=7 Hz), 7.35 (1H, t, J=7 Hz), 8.13 (1H, d, J=7 Hz), 8.42(1H, d, J=7 Hz)

The following compounds Preparations 18 (2) to (8)! were obtainedaccording to a similar manner to that of Preparation 18 (1).

Preparation 18 (2)

3-Acetyl-5-fluoro-2-methyl-7-nitrobenzo b!furan

mp: 144°-146° C. NMR (CDCl₃, δ): 2.64 (3H, s), 2.93 (3H, s), 7.88 (1H,d, J=8 Hz), 8.20 (1H, d, J=8 Hz)

Preparation 18 (3)

3-Acetyl-5-chloro-2-methyl-7-nitrobenzo b!furan

mp: 171°-172° C. NMR (CDCl₃, δ): 2.65 (3H, s), 2.92 (3H, s), 8.12 (1H,s), 8.46 (1H, s)

Preparation 18 (4)

3-Ethoxalyl-2-methyl-7-nitrobenzo b!furan

mp: 88°-89° C. NMR (CDCl₃, δ): 1.45 (3H, t, J=8 Hz), 2.82 (3H, s), 4.49(2H, q, J=8 Hz), 7.48 (1H, t, J=8 Hz), 8.19 (1H, d, J=8 Hz), 8.39 (1H,d, J=8 Hz)

Preparation 18 (5)

3-Benzoyl-2-methyl-7-nitrobenzo b!furan

mp: 92°-93° C. NMR (CDCl₃, δ): 2.60 (3H, s), 7.38 (1H, t, J=8 Hz), 7.53(2H, t, J=8 Hz), 7.65 (1H, t, J=8 Hz), 7.80 (2H, d, J=8 Hz), 7.89 (1H,d, J=8 Hz), 8.13 (1H, d, J=8 Hz)

Preparation 18 (6)

3-Butyryl-2-methyl-7-nitrobenzo b!furan

mp: 121.5°-123° C. NMR (CDCl₃, δ): 1.03 (3H, t, J=7 Hz), 1.80 (2H, sex,J=7 Hz), 2.84-2.91 (5H, m), 7.42 (1H, t, J=8 Hz), 8.11 (1H, d, J=8 Hz),8.39 (1H, d, J=8 Hz)

Preparation 18 (7)

3-Cyclohexylcarbonyl-2-methyl-7-nitrobenzo b!furan

mp: 164°-166° C. NMR (CDCl₃, δ): 1.25-2.00 (10H, m), 2.89 (3H, s), 3.01(1H, m), 7.45 (1H, t, J=8 Hz), 8.13 (1H, d, J=8 Hz), 8.32 (1H, d, J=8Hz)

Preparation 18 (8)

3-Chloroacetyl-2-methyl-7-nitrobenzo b!furan

mp: 167°-168° C. NMR (CDCl₃, δ): 2.96 (3H, s), 4.60 (2H, s), 7.50 (1H,t, J=7 Hz), 8.18 (1H, d, J=7 Hz), 8.38 (1H, d, J=7 Hz)

Preparation 19

To a mixture of 2-methyl-7-nitrobenzo b!furan (1.77 g) and aluminumchloride (2.66 g) in dichloromethane (40 ml) was added dropwise asolution of dichloromethyl methyl ether (3.6 ml) in dichloromethane (10ml). The mixture was stirred at ambient temperature for 30 minutes andthe reaction mixture was poured into a mixture of ice and1N-hydrochloric acid. The separated oil was extracted withdichloromethane and the extract was washed with brine, aqueous saturatedsodium bicarbonate and brine. Then, the solution was dried over sodiumsulfate and evaporated in vacuo. The obtained oil was crystallized fromdiethyl ether to give 3-formyl-2-methyl-7-nitrobenzo b!furan (1.83 g).

mp: 166°-167° C. NMR (CDCl₃, δ): 2.91 (3H, s), 7.50 (1H, t, J=7 Hz),8.18 (1H, d, J=7 Hz), 8.50 (1H, d, J=7 Hz), 10.28 (1H, s)

Preparation 20

Into a mixture of 2-methyl-7-nitrobenzo b!furan (200 mg) and aluminumchloride (301 mg) in dichloromethane was passed hexafluoroacetone gaswhich was made from hexafluoroacetone trihydrate (4.7 ml) and conc.sulfuric acid (15 ml). The mixture was stirred at ambient temperaturefor 4 hours and then, cooled to 4° C. To the mixture was added1N-hydrochloric acid dropwise. The organic layer was separated, washedwith brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel and theobtained oil was crystallized from n-hexane to give3-(1-hydroxy-2,2,2-trifluoro-1-trifluoromethylethyl)-2-methyl-7-nitrobenzob!furan (265 mg).

mp: 79.5°-80.5° C. NMR (CDCl₃, δ): 2.76 (3H, s), 3.79 (1H, s), 7.37 (1H,t, J=7.5 Hz), 8.10 (1H, m), 8.13 (1H, d, J=7.5 Hz) FAB-Mass: (m/z)=344(M⁺ +1)

Preparation 21

A mixture of 3-chloroacetyl-2-methyl-7-nitrobenzo b!furan (431 mg) andthiourea (194 mg) in ethanol (10 ml) was refluxed for 1.5 hours. Theseparated solid was collected, washed with ethanol and dried to give3-(2-aminothiazol-4-yl)-2-methyl-7-nitrobenzo b!furan hydrochloride (485mg).

mp: 222°-223° C. NMR (DMSO-d₆,δ): 2.72 (3H, s), 7.07 (1H, s), 7.54 (1H,t, J=7 Hz), 8.18 (1H, d, J=7 Hz), 8.23 (1H, d, J=7 Hz)

Preparation 22

A mixture of 3-(2-aminothiazol-4-yl)-2-methyl-7-nitrobenzo b!furanhydrochloride (468 mg), acetic anhydride (306 mg) and triethylamine (455mg) in 1,2-dichloroethane (20 ml) was refluxed for 1 day. To thereaction mixture was added methanol and the mixture was evaporated invacuo. The residue was purified by column chromatography on silica geland the obtained oil was crystallized from diethyl ether to give3-(2-acetylaminothiazol-4-yl)-2-methyl-7-nitrobenzo b!furan (305 mg).

mp: 260°-261° C. NMR (DMSO-d₆, δ): 2.20 (3H, s), 2.81 (3H, s), 7.53 (1H,s), 7.53 (1H, t, J=7 Hz), 8.17 (1H, d, J=7 Hz), 8.46 (1H, d, J=7 Hz)

Preparation 23 (1)

A mixture of 3-formyl-2-methyl-7-nitrobenzo b!furan (1.83 g) and sodiumborohydride (200 mg) in methanol (40 ml) was stirred at ambienttemperature for 2 hours. The reaction mixture was poured into coldwater. The separated oil was extracted with dichloromethane. The extractwas washed with brine, dried and evaporated in vacuo. The residue waspurified by column chromatography on silica gel to give3-hydroxymethyl-2-methyl-7-nitrobenzo b!furan (1.38 g) as a solid.

mp: 129°-131° C. NMR (CDCl₃, δ): 1.62 (1H, t, J=6 Hz), 2.59 (3H, s),4.83 (2H, d, J=6 Hz), 7.34 (1H, t, J=7 Hz), 7.95 (1H, d, J=7 Hz), 8.08(1H, d, J=7 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 23 (1).

Preparation 23 (2)

3-(1-Ethoxycarbonyl)hydroxymethyl-2-methyl-7-nitrobenzo b!furan

mp: 73°-78° C. NMR (CDCl₃, δ): 1.20 (3H, t, J=8 Hz), 2.62 (3H, s), 3.46(1H, d, J=4 Hz), 4.22 (2H, m), 5.35 (1H, d, J=4 Hz), 7.31 (1H, t, J=8Hz), 7.85 (1H, d, J=8 Hz), 8.07 (1H, d, J=8 Hz)

Preparation 24

A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo b!furan (200 mg) andsodium thiomethoxide (68 mg) in N,N-dimethylformamide (2 ml) was stirredat ambient temperature for 2 hours. The reaction mixture was poured intocold water and the separated oil was extracted with ethyl acetate. Theextract was washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel to give 2-methyl-3-methylthiomethyl-7-nitrobenzo b!furan(144 mg).

NMR (CDCl₃, δ): 2.03 (3H, s), 2.57 (3H, s), 3.78 (2H, s), 7.34 (1H, t,J=7.5 Hz), 7.92 (1H, d, J=7.5 Hz), 8.08 (1H, d, J=7.5 Hz)

Preparation 25

Sodium hydride (60%, 54 mg) was added to a solution of3-acetylamino-2-methyl-7-nitrobenzo b!furan (280 mg) inN,N-dimethylformamide (3 ml) at 4° C. The mixture was stirred for 30minutes and to the mixture was added iodoethane (240 mg). The mixturewas stirred at ambient temperature for 2 hours. The reaction mixture waspoured into cold water and the separated oil was extracted with ethylacetate. The extract was washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by columnchromatography on silica gel to give3-(N-acetyl-N-ethylamino)-2-methyl-7-nitrobenzo b!furan as a crystallinesolid (310 mg).

mp: 114°-116° C. NMR (CDCl₃, δ): 1.14 (3H, t, J=7.5 Hz), 1.88 (3H, s),2.54 (3H, s), 3.65 (1H, qd, J=7.5 and 13.5 Hz), 3.87 (1H, qd, J=7.5 and13.5 Hz), 7.41 (1H, t, J=8 Hz), 7.69 (1H, d, J=8 Hz), 8.15 (1H, d, J=8Hz)

Preparation 26

A solution of 3-(N-acetyl-N-ethylamino)-2-methyl-7-nitrobenzo b!furan(310 mg) and borane-methyl sulfide complex (0.13 ml, 1.42 mmol) intetrahydrofuran (6 ml) was stirred at 4° C. for 30 minutes, at ambienttemperature for 1 hour and at 50° C. for 15 minutes. Then, the mixturewas cooled to 4° C. and to the mixture was added 1N-hydrochloric acid.The mixture was stirred at ambient temperature for 1 hour andneutralized with aqueous saturated sodium bicarbonate. The separated oilwas extracted with ethyl acetate. The extract was washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue was ispurified by column chromatography on silica gel to give3-diethylamnino-2-methyl-7-nitrobenzo b!furan as an oil (249 mg).

NMR (CDCl₃, δ): 0.99 (6H, t, J=7.5 Hz), 2.50 (3H, s), 3.23 (4H, q, J=7.5Hz), 7.25 (1H, t, J=7.5 Hz), 7.84 (1H, d, J=7.5 Hz), 8.02 (1H, d, J=7.5Hz)

Preparation 27 (1)

To a solution of 3-acetyl-7-amino-2-methylbenzo b!furan (2.4 g) indichloromethane (30 ml) was added acetic anhydride (1.6 g) dropwise. Thesolution was stirred at ambient temperature for 1 hour and evaporated invacuo. Toluene was added to the residue and the solution was evaporatedin vacuo. The residue was crystallized from diethyl ether to give3-acetyl-7-acetylamino-2-methylbenzo b!furan (2.92 g).

mp: 180°-181° C. NMR (CDCl₃, δ): 2.29 (3H, s), 2.63 (3H, s), 2.79 (3H,s), 7.29 (1H, t, J=7 Hz), 7.55-7.65 (2H, m), 8.13 (1H, d, J=7 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 27 (1).

Preparation 27(2)

6-Acetyl-1-nitro-6,7,8,9-tetrahydro-5H-10-oxo-6-aza-benzo b!azulene

mp: 106°-109° C. NMR (CDCl₃, δ): 2.07-2.20 (5H, m), 3.12-3.24 (2H, m),3.79-3.92 (2H, m), 4.62 (2/3H, s), 4.81 (4/3H, s), 7.38 (1H, m), 7.75(1/3H, d, J=8 Hz), 7.88 (2/3H, d, J=8 Hz), 8.11 (1H, m)

Preparation 28 (1)

A mixture of 7-carboxy-2,3-dimethylbenzo b!furan (400 mg) andborane-dimethyl sulfide complex (0.4 ml) in tetrahydrofuran (6 ml) wasstirred at ambient temperature for 40 hours. The mixture was quenchedwith 1N-hydrochloric acid and extracted with dichloromethane. Theextract was washed with brine, dried over sodium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel and the obtained oil was crystallized from n-hexane to give2,3-dimethyl-7-hydroxymethylbenzo b!furan (322 mg).

mp: 64°-65° C. NMR (CDCl₃, δ): 1.93 (1H, t, J=7 Hz), 2.15 (3H, s), 2.40(3H, s), 4.98 (2H, d, J=8 Hz), 7.14-7.21 (2H, m), 7.36 (1H, dd, J=1.5and 8 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 28 (1).

Preparation 28 (2)

1-Nitro-6,7,8,9-tetrahydro-5H-10-oxo-6-aza-benzo b!azulene

mp: 79°-81° C. NMR (CDCl₃, δ): 1.90-2.00 (2H, m), 3.11-3.24 (4H, m),4.02 (2H, s), 7.30 (1H, t, J=8 Hz), 7.68 (1H, d, J=8 Hz), 8.05 (1H, d,J=8 Hz)

Preparation 29

To a solution of 3-acetyl-7-acetylamino-2-methylbenzo b!furan (2.92 g)in tetrahydrofuran (60 ml) was added a 3M solution of methylmagnesiumbromide in diethyl ether (12.7 ml) dropwise with ice cooling. Thesolution was stirred at ambient temperat ure for 5 hours and to thesolution was added aqueous saturated ammonium chloride. Then, themixture was poured into water and the separated oil was extracted withethyl acetate. The extract was washed with brine, dried over sodiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel and the obtained oil was crystallized frommethanol to give 7-acetylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan (1.82 g).

mp: 141°-143° C. NMR (CDCl₃, δ): 1.20 (6H, s), 1.33 (1H, s), 2.28 (3H,s), 2.60 (3H, s), 7.14 (1H, t, J=7 Hz), 7.39 (1H, d, J=7 Hz), 7.58 (1H,br), 8.05 (1H, d, J=7 Hz)

Preparation 30

A solution of 3-formyl-2-methyl-7-nitrobenzo b!furan (200 mg) and(carboethoxymethylene)triphenylphosphorane (434 mg) in dioxane (3 ml)was stirred at ambient temperature for 1 hour. The reaction mixture wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel. The obtained oil was crystallized fromdiisopropyl ether to give3-(2-ethoxycarbonylethenyl)-2-methyl-7-nitrobenzo b!furan (226 mg).

mp: 148°-150° C. NMR (CDCl₃, δ): 1.37 (3H, t, J=7.5 Hz), 2.70 (3H, s),4.30 (2H, q, J=7.5 Hz), 6.50 (1H, d, J=14 Hz), 7.43 (1H, t, J=8 Hz),7.78 (1H, d, J=14 Hz), 8.09 (1H, d, J=8 Hz), 8.14 (1H, d, J=8 Hz)

Preparation 31

10%-Palladium on carbon (30 mg) was added to a solution of3-(2-ethoxycarbonylethenyl)-2-methyl-7-nitrobenzo b!furan (210 mg) in amixture of dioxane (3 ml) and ethanol (1 ml). The mixture washydrogenated at 3 atoms for 3 hours and the catalyst was filtered off.The filtrate was concentrated in vacuo to give7-amino-3-(2-ethoxycarbonylethyl)-2-methylbenzo b!furan (195 mg).

NMR (CDCl₃, δ): 1.23 (3H, t, J=7.5 Hz), 2.40 (3H, s), 2.62 (2H, t, J=7.5Hz), 2.91 (2H, t, J=7.5 Hz), 3.89 (2H, br s), 4.12 (2H, q, J=7.5 Hz),6.58 (1H, d, J=8 Hz), 6.87 (1H, d, J=8 Hz), 7.00 (1H, t, J=8 Hz)

Preparation 32

A solution of 3-(2-ethoxycarbonyl-3-oxobutyl)-2-methyl-7-nitrobenzob!furan (170 mg) in a mixture of ethanol (5 ml) and aqueous 1N-sodiumhydroxide (5 ml) was refluxed for 1 hour. The reaction mixture wascooled and the separated solid was collected, washed with water anddried to give 2-methyl-7-nitro-3-(3-oxobutyl)benzo b!furan (105 mg).

mp: 99°-100° C. NMR (CDCl₃, δ): 2.12 (3H, s), 2.52 (3H, s), 2.77 (2H, t,J=6 Hz), 2.92 (2H, t, J=6 Hz), 7.31 (1H, t, J=7 Hz), 7.74 (1H, d, J=7Hz), 8.05 (1H, d, J=7 Hz)

Preparation 33

3-Hydroxymethyl-2-methyl-7-nitrobenzo b!furan (1.0 g) was added tothionyl chloride (1.8 ml) with ice cooling. The mixture was stirred atambient temperature for 30 minutes and concentrated in vacuo. To theresidue was added toluene and the mixture was concentrated again. Theresidue was crystallized from a mixture of diethyl ether and n-hexane togive 3-chloromethyl-2-methyl-7-nitrobenzo b!furan (1.01 g).

mp: 132°-133° C. NMR (CDCl₃, δ): 2.61 (3H, s), 4.73 (2H, s), 7.40 (1H,t, J=7 Hz), 7.91 (1H, d, J=7 Hz), 8.12 (1H, d, J=7 Hz)

Preparation 34

A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo b!furan (410 mg) andpotassium phthalimide (506 mg) in N,N-dimethylformamide (10 ml) wasstirred at ambient temperature for 3 hours. Then, the mixture was pouredinto cold water and the separated solid was collected, washed with waterand dried to give 2-methyl-7-nitro-3-phthalimidomethylbenzo b!furan (585mg).

mp: 231°-233° C. NMR (CDCl₃, δ): 2.80 (3H, s), 4.92 (2H, s), 7.33 (1H,t, J=7 Hz), 7.65-7.78 (2H, m), 7.78-7.90 (2H, m), 8.04 (1H, d, J=7 Hz),8.18 (1H, d, J=7 Hz)

Preparation 35

A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo b!furan (226 mg) andtriethyl phosphite (0.52 ml) was stirred at 100° C. for 6 hours. Thereaction mixture was cooled and concentrated in vacuo and to the residuewas added toluene. The mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel. The obtained oilwas crystallized from diisopropyl ether to give3-(diethoxyphosphorylmethyl)-2-methyl-7-nitrobenzo b!furan (93 mg).

mp: 102°-103° C. NMR (CDCl₃, δ): 1.25 (6H, t, J=7 Hz), 2.57 (3H, d, J=4Hz), 3.15 (2H, d, J=20 Hz), 4.05 (4H, quint., J=7 Hz), 7.33 (1H, t, J=7Hz), 7.88 (1H, d, J=7 Hz), 8.08 (1H, d, J=7 Hz)

Preparation 36

To a solution of sodium (52 mg) in ethanol (5 ml) was added ethylacetoacetate (293 mg) and 3-chloromethyl-2-methyl-7-nitrobenzo b!furan(339 mg). The mixture was stirred at 60° C. for 3 hours, cooled andpoured into cold water. The pH of the aqueous solution was adjusted to 3with 1N-hydrochloric acid and the separated oil was extracted withdichloromethane. The extract was washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel and the obtained oil was crystallized fromn-hexane to give 3-(2-ethoxycarbonyl-3-oxobutyl)-2-methyl-7-nitrobenzob!furan (205 mg).

mp: 97°-99° C. NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 2.22 (3H, s), 2.52(3H, s), 3.21 (3H, m), 3.79 (1H, t, J=7 Hz), 4.16 (2H, q, J=7 Hz), 7.32(1H, t, J=7 Hz), 7.77 (1H, d, J=7 Hz), 8.07 (1H, d, J=7 Hz)

Preparation 37

A mixture of 2-methyl-7-nitro-3-phthalimidomethylbenzo b!furan (575 mg)and hydrazine monohydrate (172 mg) in ethanol (10 ml) was refluxed for 5hours. The reaction mixture was cooled, acidified with 1N-hydrochloricacid and filtered. The filtrate was neutralized with aqueous saturatedsodium bicarbonate and the ethanol in the mixture was evaporated invacuo. The separated solid was collected, washed with water and dried togive 3-aminomethyl-2-methyl-7-nitrobenzo b!furan (290 mg).

mp: 134°-138° C. NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.58 (3H, s), 3.95 (2H, s),7.38 (1H, t, J=7 Hz), 7.91 (1H, d, J=7 Hz), 8.09 (1H, d, J=7 Hz)

Preparation 38 (1)

A solution of 5,7-diamino-2,3-dimethylbenzo b!furan (970 mg),di-tert-butyl dicarbonate (2.0 g) and triethylamine (668 mg) indichloromethane was stirred at ambient temperature for 8 hours. Thereaction mixture was evaporated in vacuo and the residue was purified bycolumn chromatography on silica gel. The obtained oil was crystallizedfrom a mixture of diethyl ether and n-hexane to give7-amino-5-(tert-butoxycarbonylamino)-2,3-dimethylbenzo b!furan (1.10 g).

mp: 177°-178° C. NMR (CDCl₃, δ): 1.51 (9H, s), 2.09 (3H, s), 2.32 (3H,s), 3.85 (2H, br s), 6.39 (1H, s), 6.60 (1H, s), 6.84 (1H, s)

Preparation 38 (2)

A mixture of 3-aminomethyl-2-methyl-7-nitrobenzo b!furan (278 mg) anddi-tert-butyl dicarbonate (353 mg) in dichloromethane (5 ml) was stirredat ambient temperature for overnight. The reaction mixture wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel. The obtained oil was crystallized from amixture of diisopropyl ether and n-hexane to give3-tert-butoxycarbonylaminomethyl-2-methyl-7-nitrobenzo b!furan (313 mg).

mp: 120°-122° C. NMR (CDCl₃, δ): 1.46 (9H, s), 2.58 (3H, s), 4.41 (2H,d, J=6 Hz), 4.72 (1H, br s), 7.33 (1H, t, J=7 Hz), 7.90 (1H, d, J=7 Hz),8.08 (1H, d, J=7 Hz)

Preparation 39 (1)

A mixture of 3-acetyl-2-methyl-7-nitrobenzo b!furan (413 mg),hydroxylamine hydrochloride (393 mg) and sodium bicarbonate (792 mg) inethanol (10 ml) was refluxed for 30 minutes. The reaction mixture wascooled and water was added to the solution. The separated solid wascollected, washed with water and dried to give3-(1-hydroxyiminoethyl)-2-methyl-7-nitrobenzo b!furan (320 mg).

mp: 158°-162° C.

The following compound was obtained according to a similar manner tothat of Preparation 39 (1).

Preparation 39 (2)

1-Hydroxyimino-6-nitro-1,2,3,4-tetrahydrodibenzofuran

mp: 174° C. (dec.) NMR (CDCl₃, δ): 2.07-2.20 (2H, m), 2.86 (2H, t, J=6Hz), 3.01 (2H, t, J=6 Hz), 7.38 (1H, t, J=8 Hz), 8.11 (1H, d, J=8 Hz),8.29 (1H, d, J=8 Hz)

Preparation 40 (1)

A solution of 3-(1-hydroxyiminoethyl)-2-methyl-7-nitrobenzo b!furan (200mg) in trifluoroacetic acid (3 ml) was refluxed for 1.5 hours. Thereaction mixture was concentrated in vacuo and the residue wascrystallized from a mixture of methanol and water to give3-acetylamino-2-methyl-7-nitrobenzo b!furan (185 mg).

mp: >250° C. NMR (CDCl₃ :CD₃ OD=1:1, δ): 2.23 (3H, s), 2.50 (3H, s),7.33 (1H, t, J=7 Hz), 7.75 (1H, d, J=7 Hz), 8.70 (1H, d, J=7 Hz)

Preparation 40 (2)

A solution of6-nitro-1,2,3,4-tetrahydro-1-p-toluenesulfonyloxyiminodibenzofuran (1.1g) in trifluoroacetic acid (22 ml) was refluxed for 3 hours. The mixturewas evaporated in vacuo and poured into a mixture of ice and water. Theseparated oil was extracted with chloroform. The extract was washed withaqueous saturated sodium bicarbonate, dried over sodium sulfate andevaporated in vacuo. The residue was purified by column chromatographyon silica gel and the obtained crude solid was triturated with a hotmixture of ethyl acetate and n-hexane (1:1) to give1-nitro-6,7,8,9-tetrahydro-5H-10-oxo-6-aza-benzo b!azulen-5-one (550mg).

mp: 230°-233° C. NMR (CDCl₃, δ): 2.21-2.31 (2H, m), 3.33 (2H, t, J=6Hz), 3.50 (2H, q, J=5 Hz), 6.33 (1H, m), 7.42 (1H, t, J=8 Hz), 8.13 (1H,d, J=8 Hz), 8.63 (1H, d, J=8 Hz)

Preparation 41

A mixture of 6-nitro-1-oxo-1,2,3,4-tetrahydrodibenzofuran (300 mg) andsodium azide (102 mg) in trifluoroacetic acid (3 ml) was stirred at 60°C. for 5 hours. The reaction mixture was concentrated in vacuo and theresidue was purified by column chromatography on silica gel. Theobtained oil was crystallized from diisopropyl ether to give1-nitro-6,7,8,9-tetrahydro-5H-10-oxo-5-aza-benzo b!azulen-6-one (70 mg).

mp: >250° C. NMR (CDCl₃, δ): 2.14 (2H, m), 2.68-2.78 (2H, m), 3.20 (2H,t, J=6 Hz), 7.40 (1H, t, J=8 Hz), 7.99 (1H, d, J=8 Hz), 8.12 l (1H, d,J=8 Hz)

Preparation 42 (1)

To a solution of 3-bromo-2-methyl-7-nitrobenzo b!furan (300 mg) andacetic acid (776 mg) in a mixture of ethanol (6 ml) and dioxane (1.5 ml)was added iron (722 mg) at 50° C. The mixture was refluxed for 1.5 hoursand the insoluble material was filtered off. The filtratate wasevaporated in vacuo with toluene. The residue was extracted with amixture of ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer was separated and it was extracted with ethyl acetate fromaqueous layer. The organic layer was combined and washed with saturatedaqueous sodium bicarbonate, brine, dried over sodium sulfate, andevaporated in vacuo to give 7-amino-3-bromo-2-methylbenzo b!furan (262mg) as a white solid.

mp: 70°-71° C. NMR (CDCl₃, δ): 2.48 (3H, s), 3.82 (2H, br s), 6.63 (1H,dd, J=1 and 8 Hz), 6.86 (1H, dd, J=1 and 8 Hz), 7.09 (1H, t, J=8 Hz)

The following compounds Preparations 42 (2) to (14)! were obtainedaccording to a similar manner to that of Preparation 42 (1).

Preparation 42 (2)

3-Acetyl-7-amino-2-methylbenzo b!furan

mp:112°-113° C. NMR (CDCl₃, δ): 2.63 (3H, s), 2.73 (3H, s), 3.95 (2H, brs), 6.66 (1H, d, J=7 Hz), 7.12 (1H, t, J=7 Hz), 7.29 (1H, d, J=7 Hz)

Preparation 42 (3)

7-Amino-3-hydroxymethyl-2-methylbenzo b!furan

mp: 117°-121° C. NMR (CDCl₃, δ): 1.51 (1H, t, J=5 Hz), 2.45 (3H, s),3.90 (2H, br s), 4.72 (2H, d, J=5 Hz), 6.60 (1H, d, J=7 Hz), 6.95-7.10(2H, m)

Preparation 42 (4)

3-Acetyl-7-amino-5-fluoro-2-methylbenzo b!furan

mp: 133°-134° C. NMR (CDCl₃, δ): 2.59 (3H, s), 2.76 (3H, s), 4.05 (2H,br s), 6.39 (1H, d, J=8 Hz), 6.97 (1H, d, J=8 Hz)

Prefoaration 42 (5)

6-Amino-3,4-dihydro-1H-thiopyrano 4,3-b!benzo b!furan

NMR (CDCl₃, δ): 3.02 (4H, s), 3.75 (2H, s), 3.90 (2H, br s), 6.62 (1H,dd, J=1 and 8 Hz), 6.83 (1H, dd, J=1 and 8 Hz), 7.02 (1H, t, J=8 Hz)

Preparation 42 (6)

6-Amino-1,2-dihydro-1-oxo-4H-thiopyrano 3,4-b!benzo b!furan

mp: 161°-163° C. NMR (CDCl₃, δ): 3.49 (2H, s), 3.92 (2H, br s), 3.99(2H, s), 6.70 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.48 (1H, d, J=8Hz)

Preparation 42 (7)

7-Amino-2-methyl-3-methylthiomethylbenzo b!furan NMR (CDCl₃, δ): 2.00(3H, s), 2.43 (3H, s), 3.71 (2H, s), 3.80-3.97 (2H, m), 6.60 (1H, d, J=7Hz), 6.97-7.04 (2H, m)

Preparation 42 (8)

3-Acetyl-7-amino-5-chloro-2-methylbenzo b!furan

mp: 162°-163° C. NMR (CDCl₃, δ): 2.60 (3H, s), 2.76 (3H, s), 4.02 (2H,br s), 6.65 (1H, s), 7.28 (1H, s)

Preparation 42 (9)

7-Amino-3-butyryl-2-methylbenzo b!furan

mp: 109°-111° C. NMR (CDCl₃, δ): 1.04 (3H, t, J=7 Hz), 1.80 (2H, sex,J=7 Hz), 2.77 (3H, s), 2.91 (2H, t, J=7 Hz), 3.46 (2H, br s), 6.77 (1H,d, J=8 Hz), 7.12 (1H, t, J=8 Hz), 7.27 (1H, m)

Preparation 42 (10)

7-Amino-3-(1-ethoxycarbonyl)hydroxymethyl-2-methylbenzo b!furan

mp: 103°-105° C. NMR (CDCl₃, δ): 1.19 (3H, t, J=8 Hz), 2.49 (3H, s),3.37 (1H, br s), 3.88 (2H, br s), 4.21 (2H, m), 5.28 (1H, s), 6.58 (1H,d, J=8 Hz), 6.90 (1H, d, J=8 Hz), 6.98 (1H, t, J=8 Hz)

Preparation 42 (11)

7-Amino-3-(2-ethoxycarbonylethenyl)-2-methylbenzo b! furan

mp: 103°-105° C. NMR (CDCl₃, δ): 1.35 (3H, t, J=7.5 Hz), 2.57 (3H, s),3.94 (2H, br s), 4.29 (2H, q, J=7.5 Hz), 6.48 (1H, d, J=14 Hz), 6.66(1H, d, J=8 Hz), 7.10 (1H, t, J=8 Hz), 7.19 (1H, d, J=8 Hz), 7.77 (1H,d, J=14 Hz)

Preparation 42 (12)

6-Amino-1-oxo-1,2,3,4-tetrahydrodibenzofuran

mp: 118°-119.5° C. NMR (CDCl₃, δ): 2.28 (2H, quint., J=7 Hz), 2.60 (2H,t, J=7 Hz), 3.03 (2H, t, J=7 Hz), 3.95 (2H, m), 6.68 (1H, d, J=8 Hz),7.12 (1H, t, J=8 Hz), 7.45 (1H, d, J=7 Hz)

Preparation 42 (13)

7-Amino-3-ethoxycarbonylmethyl-2-methylbenzo b!furan

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 2.42 (3H, s), 3.57 (2H, s), 3.88(2H, br s), 4.14 (2H, q, J=7 Hz), 6.58 (1H, d, J=8 Hz), 6.90 (1H, d, J=8Hz), 7.00 (1H, t, J=8 Hz)

Preparation 42 (14)

7-Amino-3-bromo-2-(2-ethoxycarbonylethyl)-benzo b!furan NMR (CDCl₃, δ):1.26 (3H, t, J=7 Hz), 2.76 (2H, t, J=7 Hz), 3.17 (2H, t, J=7 Hz), 3.91(2H, br s), 4.17 (2H, q, J=7 Hz), 6.64 (1H, d, J=8 Hz), 6.88 (1H, d, J=8Hz), 7.09 (1H, t, J=8 Hz)

Preparation 43 (1)

To a solution of 2-ethyl-3-methyl-7-nitrobenzo b!furan (1.00 g) in amixture of methanol (15 ml) and dioxane (10 ml) was added 10% palladiumcarbon (100 mg) and the above mixture was hydrogenated at 3 atom for 1hour. The catalyst was filtered off and the filtrate was evaporated invacuo to give 7-amino-2-ethyl-3-methylbenzo b!furan (858 mg) as an oil.

NMR (CDCl₃, δ): 1.30 (3H, t, J=8 Hz), 2.14 (3H, s), 2.74 (2H, q, J=8Hz), 3.88 (2H, br s), 6.59 (1H, d, J=6 Hz), 6.86 (1H, d, J=6 Hz), 7.01(1H, t, J=6 Hz)

The following compounds Preparations 43 (2) to (17)! were obtainedaccording to a similar manner to that of Preparation 43 (1).

Preparation 43 (2)

7-Amino-2-methyl-3-propionylbenzo b!furan

mp: 126°-127° C. NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 2.78 (3H, s),2.98 (2H, q, J=7 Hz), 3.97 (2H, br s), 6.66 (1H, t, J=7 Hz), 7.12 (1H,d, J=7 Hz), 7.28 (1H, d, J=7 Hz)

Preparation 43 (3)

7-Amino-2,3-dimethyl-5-ethoxycarbonylbenzo b!furan

mp: 137°-140° C. NMR (CDCl₃, δ): 1.42 (3H, t, J=8 Hz), 2.15 (3H, s),2.39 (3H, s), 3.95 (2H, br s), 4.38 (2H, q, J=8 Hz), 7.30 (1H, s), 7.60(1H, s)

Preparation 43 (4)

7-Amino-3-(diethoxyphosphorylmethyl)-2-methylbenzo b!furan

mp: 105°-109° C. NMR (CDCl₃, δ): 1.22 (6H, t, J=7 Hz), 2.46 (3H, d, J=4Hz), 3.10 (2H, d, J=20 Hz), 3.89 (2H, br s), 4.01 (4H, quint., J=7 Hz),6.59 (1H, d, J=7 Hz), 6.93 (1H, d, J=7 Hz), 7.01 (1H, t, J=7 Hz)

Preparation 43 (5)

3-Acetylamino-7-amino-2-methylbenzo b!furan

mp: 183°-184° C. NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.20 (3H, s), 2.37 (3H, s),6.60 (1H, d, J=7 Hz), 6.80 (1H, d, J=7 Hz), 7.00 (1H, t, J=7 Hz)

Preparation 43 (6)

7-Amino-3-tert-butoxycarbonylaminomethyl-2-methylbenzo b!furan

mp: 110°-111° C. NMR (CDCl₃, δ): 1.46 (9H, s), 2.45 (3H, s), 3.90 (2H,br s), 4.33 (2H, d, J=6 Hz), 4.65 (1H, br), 6.60 (1H, d, J=7 Hz), 6.92(1H, d, J=7 Hz), 7.03 (1H, t, J=7 Hz)

Preparation 43 (7)

7-Amino-2-methyl-3-(3-oxobutyl)benzo b!furan

mp: 75°-76° C. NMR (CDCl₃, δ): 2.12 (3H, s), 2.40 (3H, s), 2.77 (2H, m),2.85 (2H, m), 3.89 (2H, br s), 6.58 (1H, d, J=7 Hz), 6.83 (1H, d, J=7Hz), 7.00 (1H, t, J=7 Hz)

Preparation 43 (8)

7-Amino-3-diethylamino-2-methylbenzo b!furan NMR (CDCl₃, δ): 0.96 (6H,t, J=7.5 Hz), 2.38 (3H, s), 3.10 (4H, q, J=7.5 Hz), 3.89 (2H, br s),6.55 (1H, d, J=7.5 Hz), 6.29 (1H, d, J=7.5 Hz), 6.98 (1H, t, J=7.5 Hz)

Preparation 43 (9)

7-Amino-3-(1-hydroxy-2,2,2-trifluoro-1-trifluoromethylethyl)-2-methylbenzob!furan

mp: 167.5°-168.5° NMR (CDCl₃, δ): 2.00 (3H, br s), 2.63 (3H, s), 6.53(1H, d, J=7.5 Hz), 7.02 (1H, t, J=7.5 Hz), 7.16 (1H, d, J=7.5 Hz)FAB-Mass: (m/z)=314 (M⁺ +1)

Preparation 43 (10)

7-Amino-3-benzoyl-2-methylbenzo b!furan

mp: 150°-151° C. NMR (CDCl₃, δ): 2.57 (3H, s), 3.97 (2H, br s), 6.63(1H, d, J=8 Hz), 6.73 (1H, d, J=8 Hz), 6.99 (1H, t, J=8 Hz), 7.48 (2H,t, J=8 Hz), 7.59 (1H, t, J=8 Hz), 7.80 (2H, d, J=8 Hz)

Preparation 43 (11)

7-Amino-3-cyclohexylcarbonyl-2-methylbenzo b!furan

mp: 125°-126° C. NMR (CDCl₃, δ): 1.20-1.55 (5H, m), 1.60-2.05 (5H, m),2.87 (3H, s), 3.06 (1H, m), 3.97 (2H, br s), 6.65 (1H, d, J=8 Hz), 7.11(1H, t, J=8 Hz), 7.18 (1H, d, J=8 Hz)

Preparation 43 (12)

6-Amino-1,2,3,4-tetrahydrodibenzofuran NMR (CDCl₃, δ): 1.77-2.00 (4H,m), 2.54-2.79 (4H, m), 3.86 (2H, m), 6.58 (1H, d, J=8 Hz), 6.84 (1H, d,J=8 Hz), 7.00 (1H, t, J=8 Hz)

Preparation 43 (13)

1-Amino-6,7,8,9-tetrahydro-5H-10-oxo-benzo b!azulene

mp: 89°-94° C. NMR (CDCl₃, δ): 1.73-1.89 (6H, m), 2.65 (2H, t, J=5 Hz),2.91 (2H, t, J=5 Hz), 3.86 (2H, br s), 6.55 (1H, d, J=8 Hz), 6.83 (1H,d, J=8 Hz), 7.00 (1H, t, J=8 Hz)

Preparation 43 (14)

1-Amino-6,7,8,9-tetrahydro-5H-10-oxo-5-aza-benzo b!azulen-6-one

mp: 220°-223° C. NMR (CDCl₃, δ): 2.11-2.20 (2H, m), 2.71 (2H, t, J=6Hz), 3.06 (2H, t, J=6 Hz), 3.82 (2H, br s), 6.63 (1H, d, J=8 Hz), 6.83(1H, d, J=8 Hz), 7.05 (1H, t, J=8 Hz), 7.43 (1H, br s)

Preparation 43 (15)

6-Amino-1-hydroxy-1,2,3,4-tetrahydrodibenzofuran

mp: 127°-128° C. NMR (CDCl₃, δ): 1.8-2.2 (4H, m), 2.6-2.9 (2H, m), 3.90(2H, br s), 5.02 (1H, m), 6.62 (1H, t, J=4 Hz), 7.05 (2H, d, J=4 Hz)

Preparation 43 (16)

3-(2-Acetylaminothiazol-4-yl)-7-amino-2-methylbenzo b!furan

mp: 203°-204° C. NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.22 (3H, s), 2.65 (3H, s),6.68 (1H, d, J=7 Hz), 7.01 (1H, s), 7.07 (1H, t, J=7 Hz), 7.19 (1H, d,J=7 Hz)

Preparation 43 (17)

6-Acetyl-1-amino-6,7,8,9-tetrahydro-5H-10-oxo-6-aza-benzo b!azulene

mp: 137°-140° C. NMR (CDCl₃, δ): 1.98-2.17 (5H, m), 2.97-3.08 (2H, m),3.70-4.00 (4H, m), 4.51 (4/3H, s), 4.75 (2/3H, s), 6.60 (1H, t, J=8 Hz),6.81-7.08 (2H, m)

Preparation 44

To a suspension of 5,7-bis(benzoylamino)-dimethylbenzo b!furan (2.5 g)in ethanol (18 ml) was added conc. hydrochloric acid (9 ml) and themixture was refluxed for 36 hours. The reaction mixture was cooled andevaporated in vacuo. The residue was dissolved in water and the solutionwas washed with ethyl acetate. The aqueous layer was neutralized withaqueous saturated sodium bicarbonate and the separated oil was extractedwith ethyl acetate. The extract was washed with brine, dried over sodiumsulfate and evaporated in vacuo to give 5,7-diamino-2,3-dimethylbenzob!furan.

mp: 151°-152° C. NMR (CDCl₃, δ): 2.03 (3H, s), 2.31 (3H, s), 6.00 (1H,s), 6.15 (1H, s)

Preparation 45 (1)

A suspension of 7-acetylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan (1.82 g) in a mixture of ethanol (15 ml) and 3N-aqueous sodiumhydroxide (10 ml) was refluxed for 20 hours. The reaction mixture wascooled, diluted with water (20 ml) and evaporated in vacuo until theethanol of the solution was removed. The separated solid was collected,washed with water and dried to give7-amino-3-(1-hydroxy-1-methylethyl)-2-methylbenzo b!furan (1.42 g).

mp: 127°-128° C. NMR (CDCl₃, δ): 1.70 (6H, s), 1.84 (1H, s), 2.59 (3H,s), 3.90 (2H, br s), 6.58 (1H, d, J=7 Hz), 6.99 (1H, t, J=7 Hz), 7.09(1H, d, J=7 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 45 (1).

Preparation 45 (2)

7-Amino-2,3-dimethyl-5-nitrobenzo b!furan

mp: 156°-157° C. NMR (CDCl₃, δ): 2.17 (3H, s), 2.41 (3H, s), 4.12 (2H,br s), 7.48 (1H, d, J=2 Hz), 7.29 (1H, d, J=2 Hz)

Example 1 (1)

A mixture of 7-amino-2-ethyl-3-methylbenzo b!furan (858 mg),2,6-dichlorobenzoyl chloride (1.23 g) and triethylamine (1.23 g) in1,2-dichloroethane (17 ml) was stirred for 3 hours at 70° C. The mixturewas diluted with dichloromethane, washed with diluted hydrochloric acidand brine, dried over sodium sulfate, and evaporated in vacuo to give asolid. The residue solid was crystallized from a mixture of ethanol (20ml) and water (2 ml) to give7-(2,6-dichlorobenzoylamino)-2-ethyl-3-methylbenzo b!furan (610 mg).

mp: 169°-170° C. NMR (CDCl₃, δ): 1.27 (3H, t, J=7 Hz), 2.18 (3H, s),2.74 (2H, q, J=7 Hz), 7.23 (2H, m), 7.29-7.44 (3H, m), 7.81 (1H, br s),8.28 (1H, m)

The following compounds Examples 1 (2) to (76)! were obtained accordingto a similar manner to that of Example 1 (1)

Example 1 (2)

7-(2,6-Dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 169°-171° C. NMR (CDCl₃, δ): 2.46 (3H, s), 6.40 (1H, m), 7.18-7.29(2H, m), 7.32-7.44 (3H, m), 7.82 (1H, br s), 8.29 (1H, dd, J=1 and 8 Hz)

Example 1 (3)

7-(2,6-Dichlorobenzoylamino)-2,3-dimethylbenzo b!furan

mp: 195°-196° C. NMR (CDCl₃, δ): 2.16 (3H, s), 2.38 (3H, s), 7.23 (2H,m), 7.33-7.44 (3H, m), 7.81 (1H, br s), 8.28 (1H, m)

Example 4 (4)

3-Bromo-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 218°-219° C. NMR (CDCl₃, δ): 2.49 (3H, s), 7.21-7.30 (2H, m),7.30-7.45 (3H, m), 7.80 (1H, br s), 8.35 (1H, dd, J=1 and 8 Hz)

Example 1 (5)

7-(2,6-Dichlorobenzoylamino)-2,3-dimethylbenzo- b!thiophene

mp: 235°-236° C. NMR (CDCl₃, δ): 2.32 (3H, s), 2.50 (3H, s), 7.30-7.53(6H, m), 7.90 (1H, dd, J=1 and 8 Hz)

Example 1 (6)

7-(2,6-Dichlorobenzoylamino)-2,3-dimethyl-5-ethoxycarbonylbenzo b!furan

mp: 192°-193° C. NMR (CDCl₃, δ): 1.43 (3H, t, J=8 Hz), 2.20 (3H, s),2.40 (3H, s), 4.44 (2H, q, J=8 Hz), 7.25-7.45 (3H, m), 7.82 (1H, br s),8.02 (1H, s), 8.94 (1H, s)

Example 1 (7)

5-(tert-Butoxycarbonylamino)-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzob!furan

mp: 192°-194° C. NMR (CDCl₃, δ): 1.53 (9H, s), 2.12 (3H, s), 2.35 (3H,s), 6.60 (1H, s), 7.30-7.45 (3H, s), 7.68 (1H, s), 7.80 (1H, s), 7.98(1H, s)

Example 1 (8)

3-Acetyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 216°-217° C. NMR (CDCl₃, δ): 2.67 (3H, s), 2.79 (3H, s), 7.30-7.50(4H, m), 7.72 (1H, d, J=7 Hz), 7.83 (1H, br s), 8.35 (1H, d, J=7 Hz)

Example 1 (9)

7-(2,6-Dichlorobenzoylamino)-3-hydroxymethyl-2-methylbenzo b!furan

mp: 183°-184° C. NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.46 (3H, s), 4.72 (2H, s),7.25 (1H, t, J=7 Hz), 7.30-7.50 (4H, m), 8.16 (1H, d, J=7 Hz)

Example 1 (10)

7-(2,6-Dichlorobenzoylamino)-2-methyl-3-propionylbenzo b!furan

mp: 216°-217° C. NMR (CDCl₃, δ): 1.28 (3H, t, J=7 Hz), 2.79 (3H, s),2.99 (2H, q, J=7 Hz), 7.30-7.45 (4H, m), 7.70 (1H, d, J=7 Hz), 7.83 (1H,br s), 8.36 (1H, d, J=7 Hz)

Example 1 (11)

7-(2,6-Dichloro-3-methoxybenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 167°-168° C. NMR (CDCl₃, δ): 1.71 (6H, s), 1.80 (1H, s), 2.58 (3H,s), 3.94 (3H, s), 6.96 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz), 7.35 (1H,d, J=8 Hz), 7.46 (1H, d, J=8 Hz), 7.79 (1H, br s), 8.29 (1H, d, J=8 Hz)

Example 1 (12)

3-Acetyl-7-(2,6-dichlorobenzoylamino)-5-fluoro-2-methylbenzo b!furan

mp: 223°-229° C. NMR (CDCl₃, δ): 2.62 (3H, s), 2.77 (3H, s), 7.30-7.45(4H, m), 7.84 (1H, br s), 8.22 (1H, d, J=9 Hz)

Example 1 (13)

3-Acetyl-7-(2-chloro-6-methylbenzoylamino)-2-methylbenzo b!furan

mp: 181°-182° C. NMR (CDCl₃, δ): 2.48 (3H, s), 2.66 (3H, s), 2.78 (3H,s), 7.21 (1H, m), 7.32 (2H, d, J=6 Hz), 7.38 (1H, t, J=8 Hz), 7.70 (1H,d, J=8 Hz), 7.80 (1H, br s), 8.35 (1H, d, J=8 Hz)

Example 1 (14)

7-(2,6-Dichlorobenzoylamino)-3-(diethoxyphosphorylmethyl)-2-methylbenzob!furan

mp: 172°-174° C. NMR (CDCl₃, δ): 1.25 (6H, t, J=7 Hz), 2.45 (3H, d, J=4Hz), 3.12 (2H, d, J=20 Hz), 4.03 (4H, quint., J=7 Hz), 7.20-7.45 (5H,m), 7.82 (1H, br s), 8.30 (1H, d, J=7 Hz)

Example 1 (15)

6-(2,6-Dichloro-3-nitrobenzoylamino-1,2,3,4-tetrahydrodibenzofuran

mp: 244°-245° C. NMR (CDCl₃, δ): 1.81-2.00 (4H, m), 2.60-2.69 (2H, m),2.69-2.77 (2H, m), 7.24-7.29 (2H, m), 7.56 (1H, dd, J=4 and 8 Hz),7.86-7.93 (2H, m), 8.23 (1H, m)

Example 1 (16)

6-(2,6-Dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: 195°-196° C. NMR (CDCl₃, δ): 1.78-2.01 (4H, m), 2.59-2.77 (4H, m),7.20-7.30 (2H, m), 7.32-7.43 (3H, m), 7.85 (1H, br s), 8.30 (1H, m)

Example 1 (17)

6-(2,6-Dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano 4,3-b!benzofuran

mp: 215°-216° C. NMR (CDCl₃, δ): 3.00-3.06 (4H, m), 3.78 (2H, br s),7.20-7.31 (3H, m), 7.32-7.46 (2H, m), 7.82 (1H, br s), 8.43 (1H, dd, J=1and 6 Hz)

Example 1 (18)

6-(3,5-Dichloroisonicotinoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: 201°-203° C. NMR (CDCl₃, δ): 1.82-2.00 (4H, m), 2.60-2.68 (2H, m),2.68-2.77 (2H, m), 7.25 (2H, m), 7.88 (1H, br s), 8.22 (1H, dd, J=1 and7 Hz), 8.60 (2H, s)

Example 1 (19)

6-(2,6-Dichlorobenzoylamino)-1,2-dihydro-1-oxo-4H-thiopyrano 3,4-b!enzob!furan

mp: >250° C. NMR (CDCl₃, δ): 3.52 (2H, s), 4.00 (2H, s), 7.30-7.45 (4H,m), 7.77 (1H, br s), 7.90 (1H, d, J=8 Hz), 8.33 (1H, d, J=8 Hz)

Example 1 (20)

6-(2-Chloro-6-methylbenzoylamino)-1-hydroxy-1,2,3,4-tetrahydrodibenzofuran

mp: 179°-180° C. NMR (CDCl₃, δ): 1.71 (1H, d, J=7.5 Hz), 1.85-2.20 (4H,m), 2.46 (3H, s), 2.72 (2H, m), 5.05 (1H, m), 7.18 (1H, d, J=7.5 Hz),7.2-7.35 (3H, m), 7.42 (1H, d, J=7.5 Hz), 7.80 (1H, br s), 8.30 (1H, d,J=7.5 Hz)

Example 1 (21)

6-(2-Bromo-6-methylbenzoylamino)-1-hydroxy-1,2,3,4-tetrahydrodibenzofuran

mp: 186°-187° C. NMR (CDCl₃, δ): 1.71 (1H, d, J=7.5 Hz), 1.8-2.2 (4H,m), 2.47 (3H, s), 2.73 (2H, m), 5.05 (1H, br s), 7.15-7.25 (2H, m), 7.30(1H, d, J=7.5 Hz), 7.43 (1H, d, J=7.5 Hz), 7.45 (1H, t, J=7.5 Hz), 7.77(1H, br s), 8.30 (1H, d, J=7.5 Hz)

Example 1 (22)

1-(2,6-Dichlorobenzoylamino)-6,7,8,9-tetrahydro-5H-10-oxobenzo b!azulene

mp: 191°-192° C. NMR (CDCl₃, δ): 1.72-1.90 (6H, m), 2.63-2.73 (2H, m),2.87-2.95 (2H, m), 7.19-7.28 (2H, m), 7.30-7.42 (3H, m), 7.80 (1H, brs), 8.27 (1H, d, J=8 Hz)

Example 1 (23)

1-(2,6-Dichlorobenzoylamino)-6,7,8,9-tetrahydro-5H-10-oxo-5-azabenzob!azulen-6-one

mp: >250° C. NMR (CDCl₃, δ): 2.12-2.21 (2H, m), 2.70 (2H, t, J=6 Hz),3.07 (2H, t, J=6 Hz), 7.30 (1H, t, J=8 Hz), 7.34-7.45 (4H, m), 8.19 (1H,d, J=8 Hz)

Example 1 (24)

6-(2,6-Dichlorobenzoylamino)-1-oxo-1,2,3,4-tetrahydrodibenzofuran

mp: >250° C. NMR (CDCl₃, δ): 2.29 (2H, quint., J=7 Hz), 2.29 (2H, t, J=7Hz), 3.04 (2H, t, J=7 Hz), 7.34-7.44 (4H, m), 7.80 (1H, br s), 7.87 (1H,d, J=8 Hz), 8.32 (1H, d, J=8 Hz)

Example 1 (25)

7-(2,6-Dichlorobenzoylamino)-2,3-dimethyl-5-nitrobenzo b!furan

mp: >250° C. NMR (CDCl₃, δ): 2.21 (3H, s), 2.43 (3H, s), 7.35-7.47 (3H,m), 7.89 (1H, br s), 8.19 (1H, d, J=2 Hz), 9.24 (1H, d, J=2 Hz)

Example 1 (26)

3-Acetylamino-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: >250° C. NMR (DMSO-d₆, δ): 2.09 (3H, s), 2.33 (3H, s), 7.15-7.30(2H, m), 7.40-7.65 (3H, m), 7.78 (1H, d, J=7 Hz), 9.58 (1H, s)

Example 1 (27)

3-tert-Butoxycarbonylaminomethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan

mp: 188°-189° C. NMR (CDCl₃, δ): 1.46 (9H, s), 2.45 (3H, s), 4.38 (2H,d, J=6 Hz), 4.70 (1H, br s), 7.20-7.45 (5H, m), 7.82 (1H, br s), 8.31(1H, d, J=7 Hz)

Example 1 (28)

7-(2,6-Dichlorobenzoylamino)-3-diethylamino-2-methylbenzo b!furan

mp: 134°-135° C. NMR (CDCl₃, δ): 0.97 (6H, t, J=7.5 Hz), 2.38 (3H, s),3.12 (4H, q, J=7.5 Hz), 7.19 (1H, t, J=7.5 Hz), 7.13-7.43 (4H, m), 7.84(1H, br s), 8.28 (1H, d, J=7.5 Hz)

Example 1 (29)

7-(2,6-Dichlorobenzoylamino)-2-methyl-3-(3-oxobutyl)benzo b!furan

mp: 209°-210° C. NMR (CDCl₃, δ): 2.12 (3H, s), 2.41 (3H, s), 2.80 (2H,t, J=6 Hz), 2.88 (2H, t, J=6 Hz), 7.20-7.30 (2H, m), 7.30-7.40 (3H, m),7.81 (1H, br s), 8.30 (1H, d, J=7 Hz)

Example 1 (30)

3-Acetyl-5-chloro-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 241°-242° C. NMR (CDCl₃, δ): 2.63 (3H, s), 2.78 (3H, s), 7.30-7.45(3H, m), 7.73 (1H, s), 7.80 (1H, br s), 8.43 (1H, s)

Example 1 (31)

7-(2,6-Dichlorobenzoylamino)-3-(2-ethoxycarbonylethyl)-2-methylbenzob!fura

mp: 132°-134° C. NMR (CDCl₃, δ): 1.23 (3H, t, J=6.5 Hz), 2.42 (3H, s),2.64 (2H, t, J=6.5 Hz), 2.95 (2H, t, J=6.5 Hz), 4.13 (2H, q, J=6.5 Hz),7.25 (2H, d, J=6 Hz), 7.31-7.43 (3H, m), 7.82 (1H, br s), 8.29 (1H, dd,J=4.5 and 6 Hz)

Example 1 (32)

7-(2,6-Dichlorobenzoylamino)-2-methyl-3-methylthiomethylbenzo b!furan

mp: 207°-208.5° C. NMR (CDCl₃, δ): 2.04 (3H, s), 2.44 (3H, s), 3.75 (2H,s), 7.24-7.28 (1H, m), 7.33-7.44 (4H, m), 7.80 (1H, br s), 8.30 (1H, d,J=7.5 Hz)

Example 1 (33)

7-(2,6-Dichlorobenzoylamino)-3-(2-ethoxycarbonylethenyl)-2-inethylbenzob!furan

mp: 207°-208° C. NMR (CDCl₃, δ): 1.36 (3H, t, J=7.5 Hz), 2.59 (3H, s),4.28 (2H, q, J=7.5 Hz), 6.52 (1H, d, J=15 Hz), 7.31-7.43 (4H, m), 7.58(1H, d, J=8 Hz), 7.75 (1H, d, J=15 Hz), 7.83 (1H, br s), 8.37 (1H, d,J=8 Hz)

Example 1 (34)

7-(2,6-Dichlorobenzoylamino)-3-(1-hydroxy-2,2,2-trifluoro-1-trifluoromethylethyl)-2-methylbenzob!furan

mp: 208°-209° C. NMR (CDCl₃, δ): 2.65 (3H, s), 3.57 (1H, s), 7.25-7.45(4H, m), 7.50 (1H, m), 7.80 (1H, br s), 8.33 (1H, d, J=7.5 Hz)FABB-Mass: (e/z)=486 (M⁺ +1)

Example 1 (35)

3-Butyryl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 187°-188.5° C. NMR (CDCl₃, δ): 1.06 (3H, t, J=7 Hz), 1.81 (2H, sex,J=7 Hz), 2.78 (3H, s), 2.93 (2H, t, J=7 Hz), 7.32-7.45 (4H, m), 7.69(1H, d, J=8 Hz), 7.82 (1H, br s), 8.35 (1H, d, J=8 Hz)

Example 1 (36)

3-Benzoyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 213°-215° C. NMR (CDCl₃, δ): 2.57 (3H, s), 7.15 (1H, d, J=8 Hz),7.25 (1H, t, J=8 Hz), 7.30-7.45 (3H, m)), 7.50 (2H, t, J=8 Hz), 7.61(1H, t, J=8 Hz), 7.80-7.90 (3H, m), 8.31 (1H, d, J=8 Hz)

Example 1 (37)

7-(2,6-Dichlorobenzoylamino)-3-(1-ethoxycarbonyl)hydroxymethyl-2-methylbenzob!furan

mp: 169°-171° C. NMR (CDCl₃, δ): 1.22 (3H, t, J=8 Hz), 2.50 (3H, s),3.41 (1H, d, J=4 Hz), 4.23 (2H, m), 5.30 (1H, d, J=4 Hz), 7.20-7.45 (5H,m), 7.80 (1H, s), 8.28 (1H, d, J=8 Hz)

Example 1 (38)

3-Cyclohexylcarbonyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 210°-211° C. NMR (CDCl₃, δ): 1.20-1.60 (5H, m), 1.60-2.05 (5H, m),2.78 (3H, s), 3.09 (1H, m), 7.30-7.50 (4H, m), 7.60 (1H, d, J=8 Hz),7.85 (1H, br s), 8.36 (1H, d, J=8 Hz)

Example 1 (39)

7-(2,6-Dichlorobenzoylamino)-2,3-dihydro-2-methylbenzo b!furan

mp: 119°-120° C. NMR (CDCl₃, δ): 1.47 (3H, d, J=7 Hz), 2.88 (1H, dd, J=8and 15 Hz), 3.66 (1H, dd, J=8 and 15 Hz), 4.99 (1H, m), 6.90 (1H, t, J=8Hz), 6.97 (1H, d, J=8 Hz), 7.25-7.40 (3H, m), 7.48 (1H, br s), 8.25 (1H,d, J=8 Hz)

Example 1 (40) 7-(2-Chloro-6-fluorobenzoylamino)-2,3-dimethylbenzob!furan

mp: 161°-162° C. NMR (CDCl₃, δ): 2.15 (3H, s), 2.37 (3H, s), 7.12 (1H,t, J=8 Hz), 7.20-7.30 (3H, m), 7.39 (1H, m), 7.88 (1H, br s), 8.27 (1H,m)

Example 1 (41)

3-Acetyl-7-(2-bromo-6-methylbenzoylamino)-2-methylbenzo b!furan

mp: 198° C. NMR (CDCl₃, δ): 2.49 (3H, s), 2.67 (3H, s), 2.78 (3H, s),7.2-7.3 (2H, m), 7.38 (1H, t, J=7.5 Hz), 7.48 (1H, dd, J=2 and 7.5 Hz),7.71 (1H, d, J=7.5 Hz), 7.77 (1H, br s), 8.35 (1H, d, J=7.5 Hz)

Example 1 (42)

7-(2-Chloro-6-methoxybenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 148.5°-150° C. NMR (CDCl₃, δ): 1.70 (6H, s), 1.78 (1H, s), 2.57 (3H,s), 3.84 (3H, s), 6.90 (1H, d, J=8 Hz), 7.06 (1H, d, J=8 Hz), 7.20 (1H,t, J=8 Hz), 7.32 (1H, t, J=8 Hz), 7.42 (1H, d, J=8 Hz), 7.87 (1H, br s),8.32 (1H, d, J=8 Hz)

Example 1 (43)

3-(1-Hydroxy-1-methyiethyl)-2-methyl-7-(6-methyl-2-nitrobenzoylamino)benzob!furan

mp: 180°-182.5° C. NMR (CDCl₃, δ): 1.71 (6H, s), 1.80 (1H, s), 2.56 (6H,s), 7.23 (1H, t, J=8 Hz), 7.48 (1H, d, J=8 Hz), 7.52 (1H, t, J=8 Hz),7.61 (1H, d, J=8 Hz), 7.74 (1H, br s), 8.09 (1H, d, J=8 Hz), 8.22 (1H,d, J=8 Hz)

Example 1 (44)

7-(2-Chloro-6-phenylbenzoylamino)-2,3-dimethylbenzo b!furan

mp: 118°-120° C. NMR (CDCl₃, δ): 2.09 (3H, s), 2.29 (3H, s), 7.10-7.14(2H, m), 7.22-7.40 (4H, m), 7.40-7.47 (2H, m), 7.47-7.55 (3H, m), 7.99(1H, m)

Example 1 (45)

3-Acetyl-7-(2,6-dichloro-3-nitrobenzoylamino)-2-methylbenzo b!furan

mp: >250° C. NMR (DMSO-d₆, δ): 2.62 (3H, m), 2.80 (3H, m), 7.37 (1H, t,J=8 Hz), 7.85 (1H, d, J=8 Hz), 7.89 (1H, d, J=8 Hz), 7.94 (1H, d, J=8Hz), 8.22 (1H, d, J=8 Hz)

Example 1 (46)

7-(2,6-Dichloro-3-nitrobenzoylamino)-2,3-dimethylbenzo b!furan

mp: 225°-226° C. NMR (CDCl₃, δ): 2.17 (3H, s), 2.38 (3H, s), 7.21-7.28(2H, m), 7.57 (1H, d, J=8 Hz), 7.85 (1H, br s), 7.90 (1H, br s), 8.22(1H, m)

Example 1 (47)

2,3-Dimethyl-7-(2,4,6-trichlorobenzoylamino)benzo- b!furan

mp: 215°-217° C. NMR (CDCl₃, δ): 2.16 (3H, s), 2.38 (3H, s), 7.20-7.27(2H, m), 7.41 (2H, s), 7.79 (1H, br s), 8.23 (1H, m)

Example 1 (48)

7-(2,6-Dichloro-3-methylbenzoylamino)-2,3-dimethylbenzo b!furan

mp: 188°-190° C. NMR (CDCl₃, δ): 2.14 (3H, s), 2.35 (3H, s), 2.40 (3H,s), 7.20-7.30 (4H, m), 7.80 (1H, br s), 8.30 (1H, d, J=8 Hz)

Example 1 (49)

7-(2,6-Dichloro-3-triisopropylsilyloxybenzoyl-amino)-2,3-dimethylbenzob!furan NMR (CDCl₃, δ): 1.12 (18H, d, J=7 Hz), 1.26-1.39 (3H, m), 2.14(3H, s), 2.37 (3H, s), 6.90 (1H, d, J=8 Hz), 7.19-7.27 (3H, m), 7.77(1H, br s), 8.29 (1H, d, J=8 Hz)

Example 1 (50)

2,3-Dimetyl-7-(2,4,6-triisopropylbenzoylamino)-benzo b!furan

mp: 136°-137° C. NMR (CDCl₃, δ): 1.28 (18H, d, J=7.5 Hz), 2.14 (3H, s),2.33 (3H, s), 2.94 (1H, m), 3.14 (2H, m), 7.10 (2H, s), 7.20 (1H, t,J=7.5 Hz), 7.23 (1H, d, J=7.5 Hz), 7.84 (1H, br s), 8.31 (1H, d, J=7.5Hz)

Example 1 (51)

7-(2,6-Dichloro-3-dimethylaminomethylbenzoyl-amino)-2,3-dimethylbenzob!furan hydrochloride

mp: >250° C. NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.15 (3H, s), 2.38 (9H, s),4.42 (2H, s), 7.23 (2H, m), 7.54 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz),8.12 (1H, m)

Example 1 (52)

2,3-Dimethyl-7-(2,4,6-trimethylbenzoylamino)-benzo b!furan

mp: 151°-152° C. NMR (CDCl₃, δ): 2.15 (3H, s), 2.33 (3H, s), 2.34 (3H,s), 2.39 (6H, s), 6.93 (2H, s), 7.1-7.3 (2H, m), 7.75 (1H, br s), 8.29(1H, d, J=7.5 Hz)

Example 1 (53)

7-2,6-Dichloro-3-(2-methoxyethyl)oxymethoxy-meethylbenzoylamino!-2,3-dimethylbenzob!furan NMR (CDCl₃, δ): 2.15 (3H, s), 2.37 (3H, s), 3.40 (3H, s),3.55-3.60 (2H, m), 3.72-3.78 (2H, m), 4.72 (2H, s), 4.87 (2H, s),7.20-7.28 (2H, m), 7.40 (1H, d, J=8 Hz), 7.54 (1H, d, J=8 Hz), 7.89 (1H,br s), 8.29 (1H, d, J=8 Hz)

Example 1 (54)

2,3-Dimethyl-7-(2-iodobenzoylamino)benzo b!furan

mp: 171°-172.5° C. NMR (CDCl₃, δ): 2.16 (3H, s), 2.37 (3H, s), 7.13-7.27(3H, m), 7.46 (1H, t, J=8 Hz), 7.59 (1H, d, J=8 Hz), 7.89 (1H, br s),7.95 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz) FAB-Mass: (m/z)=392 (M⁺ +1)

Example 1 (55)

7-(2-Cyclohexylbenzoylamino)-2,3-dimethylbenzo b!furan

mp: 137°-138° C. NMR (CDCl₃, δ): 1.2-1.6 (5H, m), 1.65-1.85 (3H, m),1.90-2.00 (2H, m), 2.15 (3H, s), 2.35 (3H, s), 3.07 (1H, m), 7.1-7.4(3H, m), 7.4-7.5 (2H, m), 7.53 (1H, d, J=7.5 Hz), 7.87 (1H, br s), 8.25(1H, d, J=7.5 Hz)

Example 1 (56)

2,3-Dimethyl-7-(2,3,5,6-tetramethylbenzoylamino)-benzo b!furan

mp: 195° C. NMR (CDCl₃, δ): 2.15 (3H, s), 2.26 (6H, s), 2.29 (6H, s),2.39 (3H, s), 7.04 (1H, s), 7.1-7.3 (2H, m), 7.78 (1H, br s), 8.33 (1H,d, J=7.5 Hz)

Example 1 (57)

2,3-Dimethyl-7-(2-methoxy-1-naphthoylamino)-benzo b!furan

mp: 165°-167° C. NMR (CDCl₃, δ): 2.15 (3H, s), 2.32 (3H, s), 4.01 (3H,s), 7.20 (1H, d, J=8 Hz), 7.28 (1H, t, J=8 Hz), 7.33 (2H, d, J=8 Hz),7.40 (1H, t, J=8 Hz), 7.82 (1H, d, J=8 Hz), 7.96 (1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz), 8.24 (1H, br s), 8.43 (1H, d, J=8 Hz)

Example 1 (58)

7-(3,5-Dichloroisonicotinoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!lfuran

mp: 170°-171.5° C. NMR (CDCl₃, δ): 1.72 (6H, s), 1.85 (1H, s), 2.60 (3H,s), 7.23 (1H, t, J=8 Hz), 7.52 (1H, d, J=8 Hz), 7.86 (1H, br s), 8.21(1H, d, J=8 Hz), 8.62 (2H, s)

Example 1 (59)

4-(2,6-Dichlorobenzoylamino)-2,3-dimethylbenzo- b!furan

mp: 252°-253° C. NMR (DMSO-d₆, δ): 2.31 (3H, s), 2.37 (3H, s), 7.18-7.30(2H, m), 7.38 (1H, d, J=7 Hz), 7.52 (1H, dd, J=7 and 8 Hz), 7.55-7.66(2H, m)

Example 1 (60)

6-(2,6-Dichlorobenzoylamino)-2,3-dimethylbenzo- b!furan

mp: 175°-176° C. NMR (CDCl₃, δ): 2.15 (3H, s), 2.38 (3H, s), 7.20-7.40(5H, m), 7.48 (1H, s), 7.90 (1H, s)

Example 1 (61)

5-(2,6-Dichlorobenzoyla.mino)-2,3-dimethylbenzo- b!furan

mp: 229°-230° C. NMR (CDCl₃, δ): 2.17 (3H, s), 2.39 (3H, s), 7.10-7.50(6H, m), 7.89 (1H, s)

Example 1 (62)

3-(2-Acetylaminothiazol-4-yl)-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan

mp: >250° C. NMR (CDCl₃ :CD₃ OD=1:1, δ): 2.28 (3H, s), 2.68 (3H, s),7.05 (1H, s), 7.30 (1H, t, J=7 Hz), 7.35-7.50 (3H, m), 7.62 (1H, d, J=7Hz), 8.16 (1H, d, J=7 Hz)

Example 1 (63)

6-Acetyl-1-(2,6-dichlorobenzoylamino)-6,7,8,9-tetrahydro-SH-10-oxo-6-aza-benzob!azulene

mp: 252°-255° C. NMR (CDCl₃, δ): 2.00-2.17 (5H, m), 2.97-3.08 (2H, m),3.72-3.88 (2H m), 4.56 (4/3H, s), 4.77 (2/3H, s), 7.20-7.43 (5H, m),7.76-7.84 (1H, m), 8.25-8.35 (1H, m)

Example 1 (64)

7-(2-Chloronicotinoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 92°-94° C. NMR (CDCl₃, δ): 1.71 (6H, s), 1.86 (1H, 5), 2.60 (3H, s),7.25 (1H, t, J=8 Hz), 7.43 (1H, m), 7.50 (1H, d, J=8 Hz), 8.20 (1H, d,J=8 Hz), 8.29 (1H, d, J=8 Hz), 8.54 (1H, m), 8.70 (1H, br s)

Example 1 (65)

7-(3,5-Dimethyl-2-oxo-2H-pyran-4-yl)carbonylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan NMR (CDCl₃, δ): 1.72 (6H, s), 1.87 (1H, s), 2.26 (3H, s), 2.42(3H, s), 2.60 (3H, s), 6.08 (1H, s), 7.21 (1H, t, J=8 Hz), 7.51 (1H, d,J=8 Hz), 7.86 (1H, br s), 8.08 (1H, d, J=8 Hz)

Example 1 (66)

3-(1-Hydroxy-1-methylethyl)-2-methyl-7-(2-trifluoromethylbenzoylamino)benzob!furan

mp: 165°-166° C. NMR (CDCl₃, δ): 1.17 (6H, s), 1.80 (1H, s), 2.57 (3H,s), 7.21 (1H, t, J=8 Hz), 7.47 (1H, d, J=8 Hz), 7.60-7.82 (4H, m), 7.90(1H, br s), 8.22 (1H, d, J=8 Hz)

Example 1 (67)

7-(2-Benzoylbenzoylamino)-2,3-dimethylbenzo b!furan

mp: 219°-221.5° C. NMR (CDCl₃, δ): 2.10 (3H, s), 2.35 (3H, s), 5.38 (1H,br s), 6.26 (1H, d, J=8 Hz), 6.79 (1H, t, J=8 Hz), 6.88 (1H, d, J=8 Hz),7.30-7.41 (3H, m), 7.55 (1H, m), 7.61-7.68 (2H, m), 7.74 (2H, d, J=8Hz), 7.91 (1H, d, J=8 Hz)

Example 1 (68)

2,3-Dimethyl-7-(3,5-dimethylisoxazol-4-yl)-carbonylaminobenzo b!furanNMR (CDCl₃, δ): 2.16 (3H, s), 2.40 (3H, s), 2.59 (3H, s), 2.73 (3H, s),7.18-7.21 (2H, m), 7.77 (1H, br s), 8.09 (1H, m)

Example 1 (69)

7-(3-Chlorobenzob!thiophen-2-yl)carbonylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 191°-193° C. NMR (CDCl₃, δ): 1.74 (6H, s), 1.86 (1H, s), 2.65 (3H,s), 7.22 (1H, t, J=8 Hz), 7.48 (1H, d, J=8 Hz), 7.55 (2H, m), 7.89 (1H,dd, J=1.5 and 8 Hz), 7.95 (1H, dd, J=1.5 and 8 Hz), 8.24 (1H, d, J=8Hz), 9.50 (1H, br s)

Example 1 (70)

7-(3-Bromo-1-methylindol-2-yl)carbonylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 154°-155° C. NMR (CDCl₃, δ): 1.73 (6H, s), 1.81 (1H, s), 2.62 (3H,s), 4.11 (3H, s), 7.19-7.30 (2H, m), 7.42 (2H, d, J=5 Hz), 7.48 (1H, d,J=8 Hz), 7.68 (1H, d, J=8 Hz), 8.22 (1H, d, J=8 Hz), 9.03 (1H, br s)

Example 1 (71)

7-(6-Benzyloxy-2-chlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 161°-162° C. NMR (CDCl₃, δ): 1.71 (6H, s), 1.82 (1H, s), 2.52 (3H,s), 5.18 (2H, s), 6.91 (1H, d, J=8 Hz), 7.07 (1H, d, J=8 Hz), 7.19-7.31(5H, m), 7.33-7.40 (2H, m), 7.43 (1H, d, J=8 Hz), 7.90 (1H, br s), 8.30(1H, d, J=8 Hz)

Example 1 (72)

7-(2-Chloro-6-phenoxybenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 161°-162° C. NMR (CDCl₃, δ): 1.70 (6H, s), 1.79 (1H, s), 2.54 (3H,s), 6.82 (1H, d, J=8 Hz), 7.06 (2H, d, J=8 Hz), 7.10-7.23 (3H, m),7.23-7.38 (3H, m), 7.41 (1H, d, J=8 Hz), 7.98 (1H, br s), 8.23 (1H, d,J=8 Hz)

Example 1 (73)

7-(2,6-Dichlorobenzoylamino)-3-ethoxycarbonylmethyl-2-methylbenzob!furan

mp: 175°-177° C. NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 2.43 (3H, s),3.60 (2H, s), 4.16 (2H, q, J=7 Hz), 7.23-7.30 (2H, m), 7.30-7.43 (3H,m), 7.80 (1H, br s), 8.30 (1H, d, J=8 Hz)

Example 1 (74)

3-Bromo-7-(2,6-dichlorobenzoylamino)-2-(2-ethoxycarbonylethyl)benzob!furan

mp: 168°-170° C. NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 2.75 (2H, t, J=7Hz), 3.17 (2H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz), 7.25-7.43 (5H, m), 7.77(1H, m), 8.34 (1H, d, J=8 Hz)

Example 1 (75)

7-(2,6-Dichlorobenzenesulfonylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 166°-168° C. NMR (CDCl₃, δ): 1.67 (6H, s), 1.73 (1H, s), 2.51 (3H,s), 7.08 (1H, t, J=8 Hz), 7.25 (1H, m), 7.30 (1H, t, J=8 Hz), 7.40 (3H,d, J=8 Hz), 7.73 (1H, br s)

Example 1 (76)

7-(2,6-Dichlorobenzoyloxy)-2,3-dimethylbenzo b!furan

mp: 129°-130° C. NMR (CDCl₃, δ): 2.16 (3H, s), 2.39 (3H, s), 7.10-7.25(2H, m), 7.30-7.45 (4H, m)

Example 2 (1)

A mixture of 7-carboxy-2,3-dimethylbenzo b!furan (190 mg) and acatalytic amount of dimethylformamide in thionylchloride (10 ml) wasrefluxed for 3 hours. After evaporation in vacuo with toluene, it wasadded to a mixture of 2,6-dichloroaniline (162 mg) and triethylamine(202 mg) in 1,2-dichloroethane (3 ml) at ambient temperature. Themixture was stirred at 60° C. for 3 hours and washed with water andbrine. After drying over sodium sulfate, it was evaporated in vacuo. Theresidue was purified by column chromatography on silica gel eluting with(CH₂ Cl₂ :n-hexane=2:1) and the obtained oil was crystallized fromethanol to give 7- N-(2,6-dichlorophenyl)carbamoyl!-2,3-dimethylbenzob!furan (124 mg).

mp: 188°-190° C. NMR (CDCl₃, δ): 2.22 (3H, s), 2.49 (3H, s), 7.23 (1H,t, J=8 Hz), 7.36 (1H, t, J=8 Hz), 7.45 (1H, d, J=8 Hz), 7.62 (1H, d, J=8Hz), 8.12 (1H, d, J=8 Hz), 9.11 (1H, br s)

The following compounds Examples 2 (2) to (12)! were obtained accordingto a similar manner to that of Example 2 (1).

Example 2 (2)

6- N-(2,6-Dichlorophenyl)carbamoyl!-1,2,3,4-tetrahydrodibenzofuran

mp: 129° C. NMR (CDCl₃, δ): 1.80 (2H, m), 2.01 (2H, m), 2.68 (2H, m),2.83 (2H, m), 7.23 (1H, t, J=7.5 Hz), 7.36 (1H, t, J=7.5 Hz), 7.44 (2H,d, J=7.5 Hz), 7.62 (1H, d, J=7.5 Hz), 8.12 (1H, d, J=7.5 Hz), 9.13 (1H,br s)

Example 2 (3)

7- N-(2-Chloro-6-methylphenyl)carbamoyl!-2,3-dimethylbenzo b!furan

mp: 157°-158° C. NMR (CDCl₃, δ): 2.22 (3H, s), 2.39 (3H, s), 2.49 (3H,s), 7.18 (1H, t, J=7.5 Hz), 7.23 (1H, d, J=7.5 Hz), 7.35 (1H, d, J=7.5Hz), 7.36 (1H, t, J=7.5 Hz), 7.62 (1H, d, J=7.5 Hz), 8.11 (1H, d, J=7.5Hz), 9.02 (1H, br s)

Example 2 (4)

7- N-(2,6-Diisopropylphenyl)carbamoyl!-2,3-dimethylbenzo b!furan

mp: 158°-159° C. NMR (CDCl₃, δ): 1.23 (12H, d, J=7.5 Hz), 2.23 (3H, s),2.45 (3H, s), 3.23 (2H, m), 7.25 (2H, d, J=7.5 Hz), 7.35 (1H, t, J=7.5Hz), 7.36 (1H, t, J=7.5 Hz), 7.62 (1H, d, J=7.5 Hz), 8.12 (1H, d, J=7.5Hz), 8.73 (1H, br s)

Example 2 (5)

2,3-Dimethyl-7- N-(6-methyl-2-nitrophenyl)-carbamoyl!benzo b!furan

mp: 159°-160° C. NMR (CDCl₃, δ): 2.23 (3H, s), 2.45 (3H, s), 2.54 (3H,s), 7.30-7.40 (2H, m), 7.58 (1H, d, J=7.5 Hz), 7.63 (1H, d, J=7.5 Hz),7.87 (1H, d, J=7.5 Hz), 8.06 (1H, d, J=7.5 Hz), 10.28 (1H, br s)

Example 2 (6)

7- N-(2,6-Dibromophenyl)carbamoyl!-2,3-dimethylbenzo b!furan

mp: 209°-210° C. NMR (CDCl₃, δ): 2.22 (3H, s), 2.49 (3H, s), 7.09 (1H,t, J=7.5 Hz), 7.37 (1H, t, J=7.5 Hz), 7.63 (1H, d, J=7.5 Hz), 7.67 (2H,d, J=7.5 Hz), 8.13 (1H, d, J=7.5 Hz), 9.15 (1H, br s)

Example 2 (7)

2,3-Dimethyl-7- N-(2-methoxy-6-methylphenyl)carbamoyl!benzo b!furan

mp: 143°-144° C. NMR (CDCl₃, δ): 2.20 (3H, s), 2.35 (3H, s), 2.46 (3H,s), 3.83 (3H, s), 6.82 (1H, d, J=7.5 Hz), 6.92 (1H, d, J=7.5 Hz), 7.19(1H, t, J=7.5 Hz), 7.34 (1H, t, J=7.5 Hz), 7.58 (1H, d, J=7.5 Hz), 8.09(1H, d, J=7.5 Hz), 8.87 (1H, br s)

Example 2 (8)

7- N-(6-Chloro-2-methoxycarbonyl)carbamoyl!-2,3-dimethylbenzo b!furan

mp: 132°-133° C. NMR (CDCl₃, δ): 2.22 (3H, s), 2.51 (3H, s), 3.85 (3H,s), 7.25 (1H, t, J=7.5 Hz), 7.34 (1H, t, J=7.5 Hz), 7.62 (1H, d, J=7.5Hz), 7.65 (1H, d, J=7.5 Hz), 7.81 (1H, d, J=7.5 Hz), 8.08 (1H, d, J=7.5Hz)

Example 2 (9)

7- N-(2,4,6-Trichlorophenyl)carbamoyl!-2,3-dimethylbenzo b!furan

mp: 189°-190° C. NMR (CDCl₃, δ): 2.20 (3H, s), 2.48 (3H, s), 7.36 (1H,t, J=7.5 Hz), 7.47 (2H, s), 7.13 (1H, d, J=7.5 Hz), 8.10 (1H, d, J=7.5Hz), 9.03 (1H, br s)

Example 2 (10)

7- N-(2,6-Dichloro-3-methylphenyl)carbamoyl!-2,3-dimethylbenzo b!furan

mp: 216°-217° C. NMR (CDCl₃, δ): 2.19 (3H, s), 2.40 (3H, s), 2.45 (3H,s), 7.35 (1H, t, J=7.5 Hz), 7.40 (1H, d, J=7.5 Hz), 7.50 (1H, d, J=7.5Hz), 7.72 (1H, d, J=7.5 Hz), 7.73 (1H, d, J=7.5 Hz)

Example 2 (11)

2,3-Dimethyl-7- N-(2,4,6-trimethylphenyl)-carbamoyl!benzo b!furan

mp: 149° C. NMR (CDCl₃, δ): 2.21 (3H, s), 2.30 (6H, s), 2.32 (3H, s),2.45 (3H, s), 6.98 (2H, s), 7.35 (1H, t, J=7.5 Hz), 7.60 (1H, d, J=7.5Hz), 8.10 (1H, d, J=7.5 Hz), 8.74 (1H, br s)

Example 2 (12)

2,3-Dimethyl-7-(N-methoxy-N-methyl)carbamoylbenzo- b!furan NMR (CDCl₃,δ): 2.15 (3H, s), 2.40 (3H, s), 3.37 (3H, s), 3.63 (3H, s), 7.21 (1H, t,J=8 Hz), 7.34 (1H, d, J=8 Hz), 7.47 (1H, d, J=8 Hz)

Example 3

Lithium aluminium hydride (38 mg) was added to a solution of2,3-dimethyl 7-(N-methoxy-N-methyl)carbamoylbenzo b!furan (189 mg) indiethyl ether at 4° C. The mixture was stirred at 4° C. fcr 10 minutes,quenched with aqueous 10% tartaric acid and partitioned between diethylether and water. The organic layer was separated, washed with water,dried over sodium sulfate and evaporated in vacuo. The residue wasdissolved in tetrahydrofuran (5 ml) and added dropwise at 4° C. to amixture at (2,6-dichlorobenzyl)triphenylphosphonium bromide (407 mg) andpotassium tert-butoxide (100 mg) in tetrahydrofuran (5 ml) which waspreviously stirred at ambient temperature for 30 minutes. The mixturewas stirred at ambient temperature for 30 minutes and partitionedbetween diethyl ether and aqueous saturated sodium bicarbonate. Theorganic layer was separated, washed with water, dried over sodiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel and the obtained oil was crystallized froma mixture of ethyl acetate and n-hexane to give 7-2-(2,6-dichlorophenyl)ethenyl!-2,3-dimethylbenzo b!furan.

mp: 93°-94° C. NMR (CDCl₃, δ): 2.18 (3H, s), 2.44 (3H, s), 7.11 (1H, t,J=7.5 Hz), 7.21 (1H, t, J=7.5 Hz), 7.30-7.40 (4H, m), 7.40 (1H, d, J=16Hz), 7.63 (1H, d, J=16 Hz)

Example 4 (1)

A mixture of 7-amino-2,3-dimethylbenzo b!furan (100 mg) and6-chloro-N-methylisatoic anhydride (147 mg) in acetic acid (2 ml) wasstirred at 60° C. for 2 hours. The reaction mixture was concentrated invacuo and the residue was crystallized from a mixture of ethanol andwater to give 2,3-dimethyl-7-(2-chloro-6-methylaminobenzoylamino)benzob!furan (210 mg)

mp: 175°-178° C. NMR (CDCl₃, δ): 2.14 (3H, s), 2.37 (3H, s), 2.83 (3H,d, J=6 Hz), 5.62 (1H, m), 6.59 (1H, d, J=8 Hz), 6.73 (1H d, J=8 Hz),7.19 (3H, m), 8.16-8.22 (2H, m)

The following compound was obtained according to a similar manner tothat of Example 4 (1).

Example 4 (2)

3-Acetyl-7-(6-amino-2-chlorobenzoylamino)-2-methylbenzo b!furan

mp: 174°-175° C. NMR (CDCl₃, δ): 2.66 (3H, s), 2.80 (3H, s), 4.60-4.97(2H, m), 6.67 (1H, d, J=7.5 Hz), 6.83 (1H, d, J=7.5 Hz), 7.15 (1H, t,J=7.5 Hz), 7.37 (1H, t, J=7.5 Hz), 7.71 (1H, d, J=7.5 Hz), 8.25 (1H, brs), 8.30 (1H, d, J=7.5 Hz)

Example 5 (1)

A mixture of 7-amino-2,3-dimethylbenzo b!furan (161 mg), triethylamine(202 mg) and 3,6-dichlorophthalic anhydride (261 mg) in dichloromethane(5 ml) was stirred at ambient temperature for 1 hour. The reactionmixture was washed with 1N-hydrochloric acid and brine, dried oversodium sulfate and concentrated in vacuo. The residue was dissolved inmethanol and treated with diazomethane. The separated solid wascollected and washed with methanol to give7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo b!furan (250 mg).

mp: 211°-212° C. NMR (CDCl₃, δ): 2.18 (3H, s), 2.35 (3H, s), 7.14 (1H,d, J=8 Hz), 7.30 (1H, t, J=8 Hz), 7.49 (1H, d, J=8 Hz), 7.65 (2H, s)FAB-Mass: (m/z)=360 (M⁺ +1)

The following compound was obtained according to a similar manner tothat of Example 5 (1).

Example 5 (2)

3-(1-Hydroxy-1-methylethyl)-2-methyl-7-(3-nitrophthalimido)benzo b!furan

mp: 133°-136° C. NMR (CDCl₃, δ): 1.72 (6H, s), 1.81 (1H, s), 2.52 (3H,s), 7.17 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz), 7.82 (1H, d, J=8 Hz),8.00 (1H, t, J=8 Hz), 8.20 (1H, d, J=8 Hz), 8.26 (1H, d, J=8 Hz)

Example 6

A solution of 7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo b!furan (100mg) in 2N-amnonia in methanol was stirred at ambient temperature for 3hours. The separated solid was washed with water and dried to give7-(2,5-dichloro-6-carbamoylbenzoylamino)-2,3-dimethylbenzo b!furan (63mg).

mp: 229°-232° C.; NMR (DMSO-d₆, δ): 2.14 (3H, s), 2.29 (3H, s), 7.18(1H, t, J=8 Hz), 7.27 (1H, d, J=8 Hz), 7.61 (2H, s), 7.75-7.85 (3H, m)

Example 7

A solution of 7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo b!furan (100mg) in a mixture of aqueous 1N-sodium hydroxide (2 ml) and methanol (3ml) was stirred at ambient temperature overnight. The reaction mixturewas acidified with 1N-hydrochloric acid. The separated solid wascollected, washed with water and dried to give7-(6-carboxy-2,5-dichlorobenzoylamino)-2,3-dimethylbenzo b!furan (60mg).

mp: 186°-188° C.; NMR (DMSO-d₆, δ): 2.14 (3H, s), 2.39 (3H, s), 7.19(1H, t, J=8 Hz), 7.28 (1H, d, J=8 Hz), 7.66 (2H, s), 7.73 (1H, d, J=8Hz)

Example 8

A mixture of 7-amino-3-(1-hydroxy-l-methylethyl)-2-methylbenzo b!furan(150 mg), 3-nitrophthalic anhydride (205 mg) and potassium carbonate(202 mg) in N,N-dimethylformamide (2 ml) was stirred at ambienttemperature for 2 hours. Then, isopropyl iodide (280 mg) was added tothe mixture and the mixture was stirred for 3 hours. The mixture waspartitioned between ethyl acetate and brine. The organic layer wasseparated, dried over sodium sulfate and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel and theobtained oil was crystallized from a mixture of 2-propanol and water togive3-(1-hydroxy-1-methylethyl)-7-(6-isopropoxycarbonyl-2-nitrobenzoylamino)-2-methylbenzob!furan (136 mg).

mp: 118°-120° C.; NMR (CDCl₃, δ): 1.19 (6H, d, J=7 Hz), 1.71 (6H, s),1.82 (1H, s), 2.54 (3H, s), 5.20 (1H, m), 7.21 (1H, d, J=8 Hz), 7.44(1H, d, J=8 Hz), 7.72 (1H, t, J=8 Hz), 7.83 (1H, br s), 8.28 (1H, d, J=8Hz), 8.36 (2H, dd, J=1.5 and 8 Hz)

Example 9

A mixture of3-(1-hydroxy-1-methylethyl)-2-methyl-7-(3-nitrophthalimido)benzo b!furan(80 mg) and sodium borohydride (16 mg) in ethanol (2 ml) was stirred atambient temperature for 3 hours. The mixture was poured into water andextracted with ethyl acetate. The extract was washed with brine, driedover sodium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel and the obtained oil wascrystallized from diisopropyl ether to give3-(1-hydroxy-1-methylethyl)-7-(3-hydroxy-4-nitrophthalimidin-2-yl)-2-methylbenzob!furan (39 mg).

mp: 156°-158° C.; NMR (CDCl₃, δ): 1.72 (6H, s), 1.84 (1H, s), 2.59 (3H,s), 3.77 (1H, d, J=5 Hz), 7.24-7.33 (2H, m), 7.53 (1H, d, J=8 Hz), 7.71(1H, d, J=8 Hz), 7.81 (1H, d, J=8 Hz), 8.29 (1H, d, J=8 Hz), 8.44 (1H,d, J=8 Hz)

Example 10 (1)

Methanesulfonyl chloride (0.073 ml) was added to a solution of2,3-dimethyl-7-hydroxymethylbenzo b!furan (150 mg) and triethylamine(0.166 ml) in dichloromethane at 4° C. The mixture was stirred at 4° C.for 35 minutes. The mixture was washed with aqueous saturated sodiumbicarbonate and brine, dried over sodium sulfate and evaporated invacuo. The residue was dissolved in N,N-dimethylformamide and to thesolution was added potassium carbonate (248 mg) and 2,6-dichlorophenol(97 mg). The mixture was stirred at 60° C. for 2 hours and poured into amixture of ice and water. The separated oil was extracted with ethylacetate and the extract was washed with brine, dried over sodium sulfateand evaporated in vacuo. The residue was purified by preparative TLC andthe obtained oil was crystallized from petroleum ether to give7-(2,6-dichlorophenoxy)methyl-2,3-dimethylbenzo b!furan (69 mg).

mp: 87°-88° C.; NMR (CDCl₃, δ): 2.15 (3H, s), 2.37 (3H, s), 5.38 (2H,s), 7.00 (1H, t, J=7.5 Hz), 7.22 (1H, t, J=7.5 Hz), 7.30 (2H, d, J=7.5Hz), 7.40 (1H, d, J=7.5 Hz), 7.46 (1H, d, J=7.5 Hz)

The following compound was obtained according to a similar manner tothat of Example 10 (1).

Example 10 (2)

7-(2,6-Dichlorobenzyloxy)-2,3-dimethylbenzo b!furan

mp: 108°-110° C.; NMR (CDCl₃, δ): 2.13 (3H, s), 2.48 (3H, s), 5.50 (2H,s), 6.90 (1H, d, J=7 Hz), 7.05 (1H, d, J=7 Hz), 7.12 (1H, t, J=7 Hz),7.22 (1H, t, J=7 Hz), 7.35 (2H, d, J=7 Hz)

Example 11 (1)

A mixture of 6-amino-1,2,3,4-tetrahydrodibenzofuran (230 mg),2,5-hexanedione (145 mg) and conc. hydrochloric acid (1 drop) in ethanol(3 ml) was refluxed for 1 hour and poured into water. The mixture wasneutralized with aqueous saturated sodium bicarbonate and extracted withethyl acetate. The extract was washed with brine, dried over sodiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography on silica gel and the obtained oil was crystallized froma mixture of ethanol and water to give6-(2,5-dimethylpyrol-1-yl)-1,2,3,4-tetrahydrodibenzofuran (235 mg).

mp: 86°-880° C.; NMR (CDCl₃, δ): 1.80-1.99 (4H, m), 2.02 (6H, s),2.62-2.75 (4H, m), 5.98 (2H, s), 7.07 (1H, d, J=8 Hz), 7.27 (1H, t, J=8Hz), 7.45 (1H, d, J=8 Hz)

The following compound was obtained according to a similar manner tothat of Example 11 (1).

Example 11 (2)

6-2,6-Dichloro-3-(2,5-dimethylpyrrol-1-yl)benzoylamino!-1,2,3,4-tetrahydrodibenzofuran

mp: 244°-245° C.; NMR (CDCl₃, δ): 1.79-2.00 (4H, m), 2.02 (6H, s),2.59-2.80 (4H, m), 5.96 (2H, s), 7.25 (2H, d, J=5 Hz), 7.34 (1H, d, J=8Hz), 7.52 (1H, d, J=8 Hz), 7.89 (1H, br s), 8.28 (1H, m)

Example 12 (1)

To a solution of 3-acetyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan (100 mg) in tetrahydrofuran (3 ml) was added a 1M solution ofmethylmagnesium bromide in tetrahydrofuran (0.7 ml) dropwise with icecooling. The solution was stirred at ambient temperature for 2 hours andto the solution was added aqueous saturated ammonium chloride. Then, themixture was poured into water and the separated oil was extracted withethyl acetate. The extract was washed with brine, dried over sodiumsulfate and evaporated in vacuo. The residue was purified by colimnchromatography on silica gel and the obtained oil was crystallized froma mixture of diisopropyl ether and hexane to give7-(2,6-dichlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan (75 mg).

mp: 129°-131° C.; NMR (CDCl₃, δ): 1.72 (6H, s), 1.82 (1H, s), 2.59 (3H,s), 7.22 (1H, d, J=7 Hz), 7.30-7.50 (4H, m), 7.82 (1H, br s), 8.29 (1H,d, J=7 Hz)

The following compounds Examples 12 (2) to (12)! were obtained accordingto a similar manner to that of Example 12 (1).

Example 12 (2)

7-(2,6-Dichlorobenzoylamino)-3-(1-ethyl-1-hydroxypropyl)-2-methylbenzob!furan

mp: 139°-141° C.; NMR (CDCl₃, δ): 0.86 (6H, t, J=7 Hz), 1.60 (1H, s),1.86 (2H, m), 2.08 (2H, m), 2.59 (3H, s), 7.20 (1H, t, J=7 Hz),7.30-7.45 (4H, m), 7.85 (1H, br s), 8.28 (1H, d, J=7 Hz)

Example 12 (3)

7-(2,6-Dichlorobenzoylamino)-5-fluoro-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 159°-161° C.; NMR (CDCl₃, δ): 1.70 (6H, s), 1.79 (1H, s), 2.57 (3H,s), 7.18 (1H, d, J=8 Hz), 7.30-7.45 (3H, m), 7.83 (1H, br s), 8.13 (1H,d, J=8 Hz)

Example 12 (4)

7-(2-Chloro-6-methylbenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 161°-162° C.; NMR (CDCl₃, δ): 1.72 (6H, s), 1.80 (1H, s), 2.46 (3H,s), 2.58 (3H, s), 7.17-7.26 (2H, m), 7.29-7.31 (2H, m), 7.47 (1H, d, J=8Hz), 7.80 (1H, br s), 8.29 (1H, d, J=8 Hz)

Example 12 (5)

7-(2,6-Dichlorobenzoylamino)-3-(3-hydroxy-3-methylbutyl)-2-methylbenzob!furan

mp: 171°-173° C.; NMR (CDCl₃, δ): 1.33 (6H, s), 1.78 (2H, m), 2.39 (3H,s), 2.70 (2H, m), 7.20-7.30 (2H, m), 7.30-7.45 (3H, m), 7.83 (1H, br s),8.29 (1H, d, J=7 Hz)

Example 12 (6)

5-Chloro-7-(2,6-dichlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 181°-184° C.; NMR (CDCl₃, δ): 1.69 (6H, s), 1.80 (1H, s), 2.57 (3H,s), 7.30-7.45 (3H, m), 7.48 (1H, s), 7.80 (1H, br s), 8.35 (1H, s)

Example 12 (7)

7-(3-Acetylamino-2,6-dichlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 136°-140° C.; NMR (CDCl₃ :CD₃ OD=19:1, δ): 1.70 (6H, s), 2.27 (3H,s), 2.58 (3H, s), 7.22 (1H, t, J=8 Hz), 7.39 (1H, d, J=8 Hz), 7.50 (1H,d, J=8 Hz), 8.11 (2H, d, J=8 Hz)

Example 12 (8)

7-(2,6-Dichloro-3-dimethylaminoacetylamino-benzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 201°-203° C.; NMR (CDCl₃, δ): 1.72 (6H, s), 1.82 (1H, s), 2.42 (6H,s), 2.59 (3H, s), 3.14 (2H, s), 7.15-7.30 (2H, m), 7.39 (1H, d, J=8 Hz),7.48 (1H, d, J=8 Hz), 7.86 (1H, s), 8.27 (1H, d, J=8 Hz), 8.50 (1H, d,J=8 Hz)

Example 12 (9)

7-(2-Bromo-6-methylbenzoylamino)-3-(1-hydroxy-1-metethylethyl)-2-methylbenzob!furan

mp: 173°-175° C.; NMR (CDCl₃, δ): 1.71 (6H, s), 2.47 (3H, s), 2.57 (3H,s), 7.1-7.3 (3H, m), 7.4-7.5 (2H, m), 7.77 (1H, br s), 8.27 (1H, d,J=7.5 Hz)

Example 12 (10)

6-(2,6-Dichlorobenzoylamino)-1-hydroxy-1-methyl-1,2,3,4-tetrahydrodibenzofuran

mp: 180°-182° C.; NMR (CDCl₃, δ): 1.72 (3H, s), 1.83 (1H, s), 1.90-2.00(3H, m), 2.02-2.10 (1H, m), 2.63-2.83 (2H, m), 7.24-7.32 (2H, m),7.32-7.43 (2H, m), 7.52 (1H, d, J=8 Hz), 7.83 (1H, br s), 8.31 (1H, d,J=8 Hz)

Example 12 (11)

6-(2,6-Dichlorobenzoylamino)-9-(1-hydroxy-1-methylethyl)-1,2,3,4-tetrahydrodibenzofuran

mp: 192°-194° C.; NMR (CDCl₃, δ): 1.72 (6H, s), 1.80-2.00 (4H, m), 2.75(2H, m), 2.98 (2H, m), 7.21 (1H, d, J=7 Hz), 7.30-7.45 (3H, m), 7.90(1H, br s), 8.21 (1H, d, J=7 Hz)

Example 12 (12)7-(6-Acetylamino-2-chlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 219°-220° C.; NMR (CDCl₃, δ): 1.72 (6H, s), 1.84 (1H, s), 2.17 (3H,s), 2.58 (3H, s), 7.20-7.28 (2H, m), 7.41 (1H, t, J=8 Hz), 7.53 (1H, d,J=8 Hz), 8.13 (1H, d, J=8 Hz), 8.22-8.29 (2H, m), 9.02 (1H, br s)

Example 13 (1)

Sodium borohydride (7 mg) was added to a solution of7-(2,6-dichlorobenzoylamino)-3-(1-ethoxycarbonyl)hydroxymethyl-2-methylbenzob!furan (76 mg) in methanol (3 ml) at 4° C. The mixture was stirred atambient temperature for 3 hours and poured into cold water. Theseparated oil was extracted with ethyl acetate and the extract waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by colum chromatography on silica gel and theobtained oil was crystallized from diethyl ether to give7-(2,6-dichlorobenzoylamino)-3-(1,2-dihydroxyethyl)-2-methylbenzob!furan (35 mg).

mp: 167°-168° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.47 (3H, s), 3.71 (1H,dd, J=4 and 11 Hz), 3.90 (1H, dd, J=8 and 11 Hz), 4.96 (1H, dd, J=4 and8 Hz), 7.22 (1H, t, J=8 Hz), 7.30-7.50 (4H, m), 8.15 (1H, d, J=8 Hz)

The following compounds Examples 13 (2) to (7)! were obtained accordingto a similar manner to that of Example 13 (1).

Example 13 (2)

7-(2,6-Dichlorobenzoylamino)-3-(1-hydroxyethyl)-2-methylbenzo b!furan

mp: 209°-211° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 1.62 (3H, d, J=6 Hz), 2.46(3H, s), 5.11 (1H, q, J=6 Hz), 7.25 (1H, t, J=7 Hz), 7.30-7.45 (3H, m),7.52 (1H, d, J=7 Hz), 8.23 (1H, d, J=7 Hz)

Example 13 (3)

7-(2,6-Dichlorobenzoylamino)-3-(1-hydroxybutyl)-2-methylbenzo b!furan

mp: 165°-166.5° C.; NMR (CDCl₃, δ): 0.95 (3H, t, J=7 Hz), 1.20-1.48 (2H,m), 1.80 (1H, d, J=2 Hz), 1.82-2.09 (2H, m), 2.43 (3H, s), 4.89 (1H, m),7.25 (1H, m), 7.30-7.43 (3H, m), 7.48 (1H, d, J=8 Hz), 7.80 (1H, br s),8.29 (1H, d, J=8 Hz)

Example 13 (4)

7-(2,6-Dichlorobenzoylamino)-3-(1-hydroxy)phenylmaethyl-2-methylbenzob!furan

mp: 90°-100° C.; NMR (CDCl₃, δ): 2.24 (1H, d, J=3 Hz), 2.48 (3H, s),6.08 (1H, d, J=3 Hz), 7.10-7.20 (2H, m), 7.25-7.50 (8H, m), 7.81 (1H, brs), 8.25 (1H, dd, J=2 and 8 Hz)

Example 13 (5)

6-(2,6-Dichlorobenzoylamino)-1,2-dihydro-1-hydroxy-4H-thiopyrano3,4-b!benzo b!furan

mp: 214°-216° C.; NMR (CDCl₃, δ): 2.44 (1H, d, J=10 Hz), 2.96 (1H, dd,J=4 and 14 Hz), 3.15 (1H, dd, J=4 and 14 Hz), 3.56 (1H, d, J=16 Hz),3.88 (1H, d, J=16 Hz), 5.09 (1H, td, J=4 and 10 Hz), 7.30-7.45 (4H, m),7.47 (1H, d, J=8 Hz), 7.78 (1H, br s), 8.32 (1H, d, J=8 Hz)

Example 13 (6)

3-(1-Cyclohexyl)hydroxymethyl-7-(2,6-dichlorobenzoylamino)-2-methvlbenzob!furan

mp: 214°-216° C.; NMR (CDCl₃, δ): 0.80-2.20 (12H, m), 2.40 (3H, s), 4.54(1H, d, J=8 Hz), 7.23 (1H, t, J=8 Hz), 7.30 (1H, t, J=8 Hz), 7.30-7.50(4H, m), 7.80 (1H, br s), 8.28 (1H, d, J=8 Hz)

Example 13 (7)

6-(2,6-Dichlorobenzoylamino)-1-hydroxy-1,2,3,4-tetrahydrodibenzofuran

mp: 163°-165° C.; NMR (CDCl₃, δ): 1.70 (1H, d, J=7 Hz), 1.88-1.99 (2H,m), 1.99-2.14 (2H, m), 2.62-2.84 (2H, m), 5.03 (1H, m), 7.23-7.32 (2H,m), 7.32-7.47 (3H, m), 7.82 (1H, br s), 8.30 (1H, d, J=8 Hz)

Example 14 (1)

A mixture of 7-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-2-methylbenzob!furan (123 mg), acetic anhydride (43 mg) and pyridine (48 mg) indichloromethane (5 ml) was refluxed for 2 hours. The reaction mixturewas washed with 1N-hydrochloric acid, brine and aqueous saturated sodiumbicarbonate, dried over sodium sulfate and evaporated in vacuo. Theresidue was crystallized from diethyl ether to give3-acetoxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan (115mg).

mp: 196°-197° C.; NMR (CDCl₃, δ): 2.07 (3H, s), 2.50 (3H, s), 5.20 (2H,s), 7.27-7.45 (5H, m), 7.81 (1H, br s), 8.32 (1H, d, J=7 Hz)

The following compounds Examples 14 (2) to (7)! were obtained accordingto a similar manner to that of Example 14 (1).

Example 14 (2)

3-(1-Acetoxyethyl)-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 180°-181° C.; NMR (CDCl₃, δ): 1.17 (3H, d, J=7 Hz), 2.04 (3H, s),2.48 (3H, s), 6.03 (1H, q, J=7 Hz), 7.20-7.43 (4H, m), 7.47 (1H, d, J=8Hz), 7.80 (1H, br s), 8.30 (1H, d, J=8 Hz)

Example 14 (3)

7-(2,6-Dichlorobenzoylamino)-3-ethoxycarbonyloxymethyl-2-methylbenzob!furan

mp: 178°-179° C.; NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 2.50 (3H, s),4.19 (2H, q, J=7 Hz), 5.25 (2H, s), 7.25-7.45 (5H, m), 7.80 (1H, br s),8.30 (1H, d, J=8 Hz)

Example 14 (4)

7-(2,6-Dichlorobenzoylamino)-3-diethoxyphosphoryloxymethyl-2-methylbenzob!furan

mp: 149°-152° C.; NMR (CDCl₃, δ): 1.28 (6H, t, J=7 Hz), 2.50 (3H, s),4.06 (4H, quint., J=7 Hz), 5.17 (2H, d, J=8 Hz), 7.25-7.45 (5H, m), 7.80(1H, br s), 8.31 (1H, d, J=8 Hz)

Example 14 (5)

3-Benzoyloxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 191°-192° C.; NMR (CDCl₃, δ): 2.55 (3H, s), 5.45 (2H, s), 7.25-7.45(7H, m), 7.55 (1H, t, J=8 Hz), 7.82 (1H, br s), 8.01 (2H, d, J=8 Hz),8.32 (1H, d, J=8 Hz)

Example 14 (6)

3-Cyclohexylcarbonyloxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan

mp: 207°-209° C.; NMR (CDCl₃, δ): 1.10-1.95 (10H, m), 2.30 (1H, m), 2.50(3H, s), 5.19 (2H, s), 7.25-7.45 (5H, m), 7.81 (1H, br s), 8.30 (1H, d,J=8 Hz)

Example 14 (7)

3-(4-Carboxybutyryl)oxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan

mp: 150°-152° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 1.93 (2H, quint., J=7 Hz),2.33 (2H, t, J=7 Hz), 2.40 (2H, t, J=7 Hz), 2.50 (3H, s), 5.21 (2H, s),7.25-7.45 (5H, m), 8.23 (1H, d, J=8 Hz)

Example 15

A mixture of3-(4-carboxybutyryl)oxymethyl)-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan(2.27 g), disuccinimidyl carbonate (2.51 g) and pyridine (1.16 g) inacetonitrile (100 ml) was stirred at ambient temperature for 2 days. Thereaction mixture was concentrated in vacuo and the residue wascrystallized from a mixture of ethyl acetate and hexane to give7-(2,6-dichlorobenzoylamino)-2-methyl-3-(4-succinimidyloxy-carbonylbutyryl)oxymethylbenzob!furan (2.6 g).

mp: 117°-121° C.; NMR (CDCl₃, δ): 2.05 (2H, quint., J=7 Hz), 2.48 (2H,t, J=7 Hz), 2.50 (3H, s), 2.68 (2H, t, J=7 Hz), 2.81 (4H, s), 5.22 (2H,s), 7.29 (1H, t, J=8 Hz), 7.32-7.45 (4H, m), 7.89 (1H, br s), 8.30 (1H,d, J=8 Hz)

The following compounds Examples 16 (1) to (6)! were obtained accordingto a similar manner to that of Preparation 10.

Example 16 (1)

3-(Benzimidazol-2-ylthiomethyl)-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan

mp: 155° C.; NMR (CDCl₃, δ): 2.38 (3H, s), 4.60 (2H, s), 7.18-7.40 (8H,m), 7.70 (1H, d, J=8 Hz), 7.80 (1H, br s), 8.28 (1H, d, J=8 Hz), 9.18(1H, br s)

Example 16 (2)

7-(2,6-Dichlorobenzoylamino)-3-ethoxycarbonylmethylthiomethyl-2-methylbenzob!furan

mp: 118°-122° C.; NMR (CDCl₃, δ): 1.28 (3H, t, J=8 Hz), 2.44 (3H, s),3.08 (2H, s), 3.92 (2H, s), 4.16 (2H, q, J=8 Hz), 7.20-7.45 (5H, m),7.79 (1H, br s), 8.30 (1H, d, J=8 Hz)

Example 16 (3)

7-(2,6-Dichlorobenzoylamino)-3-(2-hydroxyethyl)thiomethyl-2-methylbenzob!furan

mp: 164°-167° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.43 (3H, s), 2.62 (2H, t,J=7 Hz), 3.70 (2H, t, J=7 Hz), 3.82 (2H, s), 7.27 (1H, t, J=8 Hz),7.30-7.45 (4H, m), 8.12 (1H, d, J=8 Hz)

Example 16 (4)

7-(2,6-Dichlorobenzoylamino)-3- (imidazol-1-yl)thiomethyl!-2-methylbenzob!furan hydrochloride

mp: 218°-221° C.; NMR (DMSO-d₆, δ): 2.23 (3H, s), 4.62 (2H, s), 7.25(1H, t, J=8 Hz), 7.41 (1H, d, J=8 Hz), 7.47-7.60 (3H, m), 7.72 (2H, s),7.82 (1H, d, J=8 Hz)

Example 16 (5)

7-(2,6-Dichlorobenzoylamino)-3-(dimethoxyphosphorylmethyl)-2-methylbenzob!furan

mp: 215°-218° C.; NMR (CDCl₃, δ): 2.43 (3H, d, J=4 Hz), 3.12 (2H, d,J=20 Hz), 3.68 (6H, d, J=9 Hz), 7.20-7.45 (5H, m), 7.82 (1H, br s), 8.29(1H, d, J=8 Hz)

Example 16 (6)

7-(2,6-Dichlorobenzoylamino)-3-methoxymethyl-2-methylbenzo b!furan

mp: 199°-200° C.; NMR (CDCl₃, δ): 2.45 (3H, s), 3.37 (3H, s), 4.54 (2H,s), 7.2-7.5 (5H, m), 7.81 (1H, br s), 8.30 (1H, d, J=7.5 Hz)

Example 17

A mixture of 3-chloromethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan (150 mg), imidazole (33 mg) and triethylamine (62 mg) in1,2-dichloroethane (1.5 ml) was refluxed for 3 hours. The reactionmixture was evaporated in vacuo and the residue was purified by columnchromatography on silica gel. The obtained oil was crystallized from amixture of ethyl acetate and diisopropyl ether and the crystalline wastreated with ethanolic hydrogen chloride. The separated solid wascollected and washed with ethanol to give7-(2,6-dichlorobenzoylamino)-3-(imidazol-1-yl)methyl-2-methylbenzob!furan hydrochloride (62 mg).

mp: >250° C.; NMR (DMSO-d₆, δ): 2.61 (3H, s), 5.61 (2H, s), 7.23 (1H, t,J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.48-7.60 (3H, m), 7.70 (1H, d, J=3 Hz),7.80 (1H, d, J=3 Hz), 7.83 (1H, d, J=8 Hz), 9.30 (1H, s)

Example 18

A mixture of 3-bromo-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan(165 mg), 2-(tributylstannyl)pyridine (213 mg) andtetrakis(triphenylphosphine)palladium (10 mg) in 1,2-dimethoxyethane (3ml) was refluxed for 18 hours. The reaction mixture was evaporated invacuo and the residue was purified by column chromatography on silicagel. The obtained oil was dissolved in methanolic hydrogen chloride andto the solution was evaporated in vacuo. The residue was crystallizedfrom ethyl acetate to give7-(2,6-dichlorobenzoylamino)-2-methyl-3-(pyridin-2-yl)benzo b!furanhydrochloride (45 mg).

mp: 240°-243° C.; NMR (DMSO-d₆, δ): 2.71 (3H, s), 7.32 (1H, t, J=8 Hz),7.49-7.61 (4H, m), 7.71 (1H, d, J=8 Hz), 7.85-7.91 (2H, m), 8.15 (1H,m), 8.81 (1H, d, J=5 Hz)

Example 19

A solution of5-(tert-butoxycarbonylamino)-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzob!furan (1.56 g) in 4N-hydrogen chloride in ethyl acetate (10 ml) wasstirred at ambient temperature for 1 hour and to the reaction mixturewas added diethyl ether. The separated solid was collected, washed withdiethyl ether and dried to give5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo b!furanhydrochloride (1.23 g).

mp: >250° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.16 (3H, S), 2.40 (3H, s),7.30-7.50 (4H, m), 8.12 (1H, s)

Example 20

A solution of3-tert-butoxycarbonylaminomethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan (312 mg) in trifluoroacetic acid (2 ml) was stirred at ambienttemperature for 10 minutes. The reaction mixture was concentrated invacuo and to the residue was added aqueous saturated sodium bicarbonate.The separated solid was collected, washed with water and dried to give3-aminomethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan (210mg).

mp: 200°-203° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.45 (3H, s), 3.89 (2H,s), 7.18-7.48 (5H, m), 8.22 (1H, d, J=7 Hz)

Example 21 (1)

A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzob!furan hydrochloride (116 mg) and acetic anhydride (74 mg) in aceticacid (1 ml) was stirred at 80° C. for 1.5 hours. The reaction mixturewas cooled and to the mixture was added water. The separated solid wascollected, washed with water and dried to give5-acetylamino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo b!furan (97mg).

mp: >250° C.; NMR (DMSO-d₆, δ): 2.05 (3H, s), 2.11 (3H, s), 2.38 (3H,s), 7.40-7.60 (3H, m), 7.79 (1H, s), 7.89 (1H, s), 10.00 (1H, s), 10.89(1H, s)

The following compounds Examples 21 (2) to (5)! were obtained accordingto a similar manner to that of Example 21 (1)

Example 21 (2)

3-Acetylaminomethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: >250° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 1.98 (3H, s), 2.47 (3H, s),4.43 (2H, s), 7.20-7.50 (5H, m), 8.15 (1H, d, J=7 Hz)

Example 21 (3)

6-(3-Acetylamino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: >250° C.; NMR (CDCl₃, δ): 1.79-2.00 (4H, m), 2.28 (3H, s), 2.58-2.77(4H, m), 7.20-7.28 (2H, m), 7.39 (1H, d, J=8 Hz), 7.66 (1H, br s), 7.88(1H, br s), 8.28 (1H, dd, J=6 and 6 Hz), 8.42 (1H, d, J=8 Hz)

Example 21 (4)

3-Acetyl-7-(3-acetylamino-2,6-dichlorobenzoylamino)-2-methylbenzob!furan

mp: >250° C.; NMR (DMSO-d₆, δ): 2.13 (3H, s), 2.12 (3H, s), 2.79 (3H,s), 7.35 (1H, t, J=8 Hz), 7.53 (1H, d, J=8 Hz), 7.75-7.90 (3H, m), 9.72(1H, s)

Example 21 (5)

3-Acetyl-7-(6-acetylamino-2-chlorobenzoylamino)-2-methylbenzo b!furan

mp: 250°-252.5° C.; NMR (CDCl₃ :CD₃ OD=20:1, δ): 2.17 (3H, s), 2.67 (3H,s), 2.80 (3H, s), 7.29 (1H, d, J=8 Hz), 7.38 (1H, t, J=8 Hz), 7.42 (1H,t, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.15 (1H, d, J=8Hz)

The following compounds Examples 22 (1) to (4)! were obtained accordingto a similar manner to that of Preparation 11 (1).

Example 22 (1)

3-(2-Carboxyethyl)-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 211°-213° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.42 (3H, s), 2.67 (2H, t,J=7.5 Hz), 2.95 (2H, t, J=7.5 Hz), 7.23-7.29 (2H, m), 7.32-7.43 (3H, m),8.28 (1H, m)

Example 22 (2)

5-Carboxy-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo b!furan

mp: >250° C.; NMR (CDCl₃ :CD₃ OD=1:1, δ): 2.20 (3H, s), 2.41 (3H, s),7.30-7.50 (3H, m), 8.03 (1H, s), 8.68 (1H, s)

Example 22 (3)

7- N-(6-Carboxy-2-chlorophenyl)carbamoyl!-2,3-dimethylbenzo b!furan

mp: 194°-195° C.; NMR (CDCl₃, δ): 2.18 (3H, s), 2.43 (3H, s), 7.27 (1H,t, J=7.5 Hz), 7.30 (1H, t, J=7.5 Hz), 7.59 (1H, d, J=7.5 Hz), 7.67 (1H,d, J=7.5 Hz), 7.87 (1H, d, J=7.5 Hz), 8.07 (1H, d, J=7.5 Hz)

Example 22 (4)

3-Carboxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: >250° C.; NMR (DMSO-d₆, δ): 2.40 (3H, s), 3.63 (2H, s), 7.20 (1H, t,J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.49 (1H, m), 7.54-7.60 (2H, m), 7.78(1H, d, J=8 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 33.

Example 23

3-Chloromethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: 216°-217° C.; NMR (CDCl₃, δ): 2.49 (3H, s), 4.70 (2H, s), 7.30 (1H,t, J=8 Hz), 7.35-7.43 (4H, m), 7.80 (1H, br s), 8.33 (1H, d, J=8 Hz)

Example 24 (1)

A mixture of3-(2-carboxyethyl)-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan(90 mg), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (43 mg) and1-hydroxybenzotriazole (37 mg) in N,N-dimethylformamide (1 ml) wasstirred at ambient temperature for 30 minutes. To the mixture was addeddimethylamine hydrochloride (22 mg) and the mixture was stirred for 5hours. The reaction mixture was poured into cold water and the separatedoil was extracted with ethyl acetate. The extract was washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel and the obtained oil wascrystallized from diisopropyl ether to give7-(2,6-dichlorobenzoylamino)-3-(2-N,N-dimethylcarbamoylethyl)-2-methylbenzob!furan (67 mg).

mp: 163°-169° C.; NMR (CDCl₃, δ): 2.42 (3H, s), 2.62 (2H, t, J=7 Hz),2.91 (3H, s), 2.95 (3H, s), 2.98 (2H, t, J=7 Hz), 7.23-7.28 (2H, m),7.31-7.44 (3H, m), 7.83 (1H, br s), 8.30 (1H, m)

The following compounds Examples 24 (2) to (11)! were obtained accordingto a similar manner to that of Example 24 (1).

Example 24 (2)

3-(N-Cyclopentyl)carbamovlmethyl!-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan

mp: 247°-248° C.; NMR (DMSO-d₆, δ): 1.32-1.58 (4H, m), 1.58-1.85 (4H,m), 2.41 (3H, s), 3.41 (2H, s), 3.99 (1H, m), 7.20 (1H, t, J=8 Hz), 7.37(1H, d, J=8 Hz), 7.48 (1H, m), 7.58 (2H, d, J=8 Hz), 7.77 (1H, d, J=8Hz), 8.10 (1H, d, J=8 Hz)

Example 24 (3) 7-(2,6-Dichlorobenzoylamino)-2-methyl-3-{N-(pyridin-2-yl)methyl!carbamoylmethyl}benzo b!furan hydrochloride

mp: 221°-224° C.; NMR (DMSO-d₆, δ): 2.44 (3H, s), 3.63 (2H, s), 4.55(2H, d, J=6 Hz), 7.20 (1H, t, J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.49 (1H,m), 7.58 (2H, d, J=8 Hz), 7.68 (1H, d, J=7 Hz), 7.72 (1H, m), 7.79 (1H,d, J=8 Hz), 8.28 (1H, t, J=7 Hz), 8.73 (1H, d, J=7 Hz), 8,90 (1H, m)

Example 24 (4)

7-(2,6-Dichlorobenzoylamino)-3-{N-(2-methoxyethyl)!carbamoylmethyl}-2-methylbenzo b!furan

mp: 215°-216° C.; NMR (DMSO-d₆, δ): 3.18-3.25 (5H, m), 3.35 (2H, t, J=7Hz), 3.47 (2H, s), 7.20 (1H, t, J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.45-7.60(3H, m), 7.78 (1H, d, J=8 Hz), 8.20 (1H, br t, J=8 Hz)

Example 24 (5)

7-(2,6-Dichlorobenzoylamino)-3-{N-(2-hydroxyethyl)!carbamoylmethyl}-2-methylbenzo b!furan

mp: 175°-178° C.; NMR (DMSO-d₆, δ): 2.42 (3H, m), 3.13 (2H, t, J=7 Hz),3.40 (2H, t, J=7 Hz), 3.47 (2H, s), 4.69 (1H, t, J=7 Hz), 7.19 (1H, t,J=8 Hz), 7.36 (1H, t, J=8 Hz), 7.46-7.60 (3H, m), 7.74-7.80 (1H, m)

Example 24 (6)

7-(2,6-Dichlorobenzoylamino)-2-methyl-3-(morpholin-4-yl)carbonylmethyl!benzo b!furan

mp: 260°-261° C.; NMR (DMSO-d₆, δ): 2.39 (3H, s), 3.40-3.60 (8H, m),3.75 (2H, s), 7.18 (1H, t, J=8 Hz), 7.29 (1H, d, J=8 Hz), 7.40-7.60 (3H,m), 7.77 (1H, d, J=8 Hz)

Example 24 (7)

7-(2,6-Dichlorobenzoylamino)-2-methyl-3-{N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)!carbamoylmethyl}-benzob!furan

mp: >260° C.; NMR (DMSO-d₆, δ): 2.47 (3H, s), 4.00 (2H, s), 7.21 (1H, t,J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.40-7.60 (3H, m), 7.79 (1H, d, J=8 Hz)

Example 24 (8)

7-(2,6-Dichlorobenzoylamino)-2,3-dimethyl-5-(4-methylpiperazin-1-yl)carbonylbenzob!furan

mp: 128°-138° C.; NMR (CDCl₃, δ): 2.15 (3H, s), 2.34 (3H, s), 2.38 (3H,s), 2.40-2.60 (4H, m), 3.50-3.70 (2H, m), 3.70-3.90 (2H, m), 7.30-7.45(3H, m), 7.93 (1H, s), 8.31 (1H, s)

Example 24 (9)

7-(2,6-Dichlorobenzoylamino)-2,3-dimethyl-5-(morpholin-4-yl)carbonylbenzob!furan

mp: 219°-221° C.; NMR (CDCl₃, δ): 2.16 (3H, s), 2.39 (3H, s), 3.60-3.90(8H, m), 7.30-7.45 (3H, m), 7.90 (1H, s) 8.31 (1H, s)

Example 24 (10)

7-(2,6-Dichlorobenzoylamino)-5-(dimethylamino)acetylamino-2,3-dimethylbenzob!furan

mp: 115°-119° C.; NMR (DMSO-d₆, δ): 2.11 (3H, s), 2.30 (6H, s), 2.38(3H, s), 3.08 (2H, s), 7.42-7.62 (3H, m), 7.78 (1H, s), 7.99 (1H, s),9.80 (1H, s)

Example 24 (11)

5-(Acetylamino)acetylamino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzob!furan

mp: >250° C.; NMR (DMSO-d₆, δ): 1.89 (3H, s), 2.10 (3H, s), 2.38 (3H,s), 3.88 (2H, d, J=6 Hz), 7.43-7.62 (3H, m), 7.75 (1H, s), 7.95 (1H, s),8.20 (1H, t, J=6 Hz), 10.03 (1H, s)

Example 25

A solution of7-(2,6-dichlorobenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan (150 mg) in 4N-hydrogenchloride in ethyl acetate was refluxedfor 2 hours. The reaction mixture was concentrated in vacuo and theresidue was purified by column chromatography on silica gel. Theobtained oil was crystallized from a mixture of diethyl ether and hexaneto give 7-(2,6-dichlorobenzoylamino)-2-methyl-3-(1-methylvinyl)benzob!furan (72 mg).

mp: 147°-148° C.; NMR (CDCl₃, δ): 2.18 (3H, s), 2.49 (3H, s), 5.10 (1H,s), 5.30 (1H, s), 7.20-7.45 (5H, m), 7.82 (1H, br s), 8.30 (1H, d, J=8Hz)

Example 26

A solution of 7-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-2-methylbenzob!furan (140 mg), triethylamine (61 mg) and ethyl isocyanate (35 mg) indichloromethane was stirred at ambient temperature for 5 hours. Theraction mixture was concentrated in vacuo and the residue was purifiedby column chromatography on silica gel. The obtained oil wascrystallized from diethyl ether to give7-(2,6-dichlorobenzoylamino)-3-(N-ethylcarbamoyloxymethyl)-2-methylbenzob!furan (125 mg).

mp: 225°-226° C.; NMR (CDCl₃, δ): 1.12 (3H, t, J=8 Hz), 2.49 (3H, s),3.21 (2H, m), 4.65 (1H, m), 5.18 (2H, s), 7.25-7.45 (5H, m), 7.82 (1H,br s), 8.31 (1H, d, J=8 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 39 (1).

Example 27

7-(2,6-Dichlorobenzoylamino)-3-(1-hydroxyiminoethyl)-2-methylbenzob!furan

mp: 237°-238° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.35 (3H, s), 2.57 (3H,s), 7.27 (1H, t, J=8 Hz), 7.30-7.45 (3H, m), 7.49 (1H, d, J=8 Hz), 8.22(1H, d, J=8 Hz)

Example 28

A mixture of3-(1-cyclohexyl)hydroxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan (65 mg) and triethylsilane (87 mg) in trifluoroacetic acid (3ml) was stirred at ambient temperature for overnight. The reactionmixture was concentrated in vacuo. To the residue was added aqueoussaturated sodium bicarbonate and the separated oil was extracted withethyl acetate. The extract was washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel and the obtained oil was crystallized fromhexane to give3-cyclohexylmethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo b!furan(42 mg).

mp: 189°-190° C.; NMR (CDCl₃, δ): 0.85-1.10 (2H, m), 1.10-1.30 (3H, m),1.50-1.80 (6H, m), 2.37 (3H, s), 2.47 (2H, d, J=8 Hz), 7.20-7.30 (2H,m), 7.30-7.45 (3H, m), 7.82 (1H, br s), 8.38 (1H, m)

Example 29

A mixture of7-(2,6-dichlorobenzoylamino)-2-methyl-3-(4-succinimidyloxycarbonvlbutyryl)oxymethyl,benzo b!furan (112 mg), aminomethylenebis(phosphonic acid) (77 mg) andtriethylamine (162 mg) in N,N-dimethylformamide (2 ml) and water (0.5ml) was stirred at ambient temperature for 3 hours. Then, the reactionmixture was poured into cold water. The aqueous solution was washed withethyl acetate and the pH of the solution was adjusted to 2 with2N-hydrochloric acid. The separated solid was collected, washed withethyl acetate and water and dried to give 4-{7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan-3-yl!methyloxycarbonyl}butyrylaminomethylenebis(phosphonic acid)(50 mg).

mp: 190°-195° C.; NMR (DMSO-d₆, δ): 1.73 (2H, quint., J=7 Hz), 2.20 (2H,t, J=7 Hz), 2.32 (2H, t, J=7 Hz), 4.43 (1H, dt, J=9 and 20 Hz), 5.22(2H, s), 7.25 (1H, t, J=8 Hz), 7.41 (1H, d, J=8 Hz), 7.45-7.60 (3H, m),7.80 (1H, d, J=8 Hz)

Example 30

Nitric acid (d; 1.5, 0.033 ml) was added to a solution of6-(2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (200 mg) inacetic acid at 4° C. The mixture was stirred at ambient temperature for5 hours and poured into cold water. The separated solid was collectedand washed with isopropyl alcohol to give6-(2,6-dichlorobenzoylamino)-7-nitro-1,2,3,4-tetrahydrodibenzofuran (17mg).

mp: 246°-248° C.; NMR (CDCl₃, δ): 1.81-2.06 (4H, m), 2.61-2.72 (2H, m),2.80-2.90 (2H, m), 7.29-7.46 (4H, m), 8.06 (1H, d, J=8 Hz), 9.21 (1H, brs)

Example 31

A solution of 5-carboxy-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzob!furan (152 mg) and triethylamine (61 mg) in dichloromethane (3 ml) wasstirred at -20° C. and to the solution was added isobutyl chloroformate(66 mg). The mixture was stirred at -20° C. for 3 hours and added tocold (-20° C.) solution of 10% ammonia in methanol (3 ml). The reactionmixture was stirred at ambient temperature for 10 minutes andpartitioned between dichloromethane and water. The organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by column chromatography on silica gel and theobtained oil was crystallized from ethyl acetate to give5-carbamoyl-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo b!furan (70mg).

mp: >250° C.; NMR (CDCl₃ :CD₃ OD=1:1, δ): 2.19 (3H, s), 2.40 (3H, s),7.30-7.50 (3H, m), 7.90 (1H, s), 8.45 (1H, s)

Example 32

A mixture of 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzob!furan hydrochloride (155 mg), triethylamine (61 mg) andtrichloroacetyl isocyanate (115 mg) was stirred at ambient temperaturefor 1 hour. Then, the mixture was concentrated in vacuo and to theresidue was added methanol (3 ml) and aqueous 1N-sodium hydroxide (2ml). The mixture was stirred at 60° C. for 15 minutes and the methanolwas evaporated in vacuo. The separated solid was collected, washed withwater and dried to give7-(2,6-dichlorobenzoylamino)-2,3-dimethyl-5-ureidobenzo b!furan (130mg).

mp: >250° C.; NMR (DMSO-d₆, δ): 2.10 (3H, s), 2.37 (3H, s), 5.75 (2H,s), 7.40-7.63 (4H, m), 7.67 (1H, s), 8.63 (1H, s)

Example 33

A mixture of 3-chloromethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzob!furan (20 mg) and potassium carbonate (7.5 mg) in methanol wasrefluxed for 1 hour. The mixture was cooled and poured into water. Theseparated oil was extracted with ethyl acetate and the extract waswashed with water, dried over sodium sulfate and evaporated in vacuo.The residue was purified by preparative TLC to give7-(2,6-dichlorobenzoylamino)-2,3-dihydro-2-methoxy-2-methyl-3-methylenebenzob!furan (5 mg).

mp: 208°-210° C.; NMR (CDCl₃, δ): 1.64 (3H, s), 3.16 (3H, s), 5.20 (1H,s), 5.71 (1H, s), 7.00 (1H, t, J=7.5 Hz), 7.22 (1H, d, J=7.5 Hz),7.30-7.50 (3H, m), 7.61 (1H, br s), 8.38 (1H, d, J=7.5 Hz)

Example 34

A mixture of6-(2,6-dichlorobenzoylamino)-1-hydroxy-1,2,3,4-tetrahydrodibenzofuran(500 mg), methanesulfonyl chloride (880 mg) and triethylamine (1.19 g)in dichloromethane was refluxed for 4 hours. The mixture was washed withbrine, dried over sodium sulfate and evaporated in vacuo. The residuewas purified by column chromatography on silica gel and the obtained oilwas crystallized from a mixture of 2-propanol and water to give6-(2,6-dichlorobenzoylamino)-3,4-dihydrodibenzofuran (173 mg).

mp: 165°-167° C.; NMR (CDCl₃, δ): 2.58-2.68 (2H, m), 2.95 (2H, t, J=9Hz), 5.77 (1H, m), 6.50 (1H, d, J=9 Hz), 7.23-7.42 (5H, m), 7.82 (1H, brs), 8.29 (1H, d, J=8 Hz)

Example 35

A mixture of 6-(2,6-dichlorobenzoylamino)-3,4-dihydrodibenzofuran (100mg), 4-methylmorpholine N-oxide (39 mg) and osmium tetroxide (10%solution in tert-butanol, 1 drop) in a mixture of acetone (2 ml) andwater (0.5 ml) was stirred at ambient temperature for 6 hours. Themixture was partitioned between 1% aqueous sodium bisulfite and ethylacetate. The organic layer was separated, washed with aqueous saturatedsodium bicarbonate and brine, dried over sodium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel and the obtained oil was crystallized from diisopropyl ether to give7-(2,6-dichlorobenzoylamino)-1,2-dihydroxy-1,2,3,4-tetrahydrodibenzofuran(74 mg).

mp: 206°-209° C.; NMR (DMSO-d₆, δ): 1.80 (1H, m), 2.07 (1H, m),2.69-2.84 (2H, m), 3.83 (1H, m), 4.63 (1H, d, J=6 Hz), 4.71 (1H, m),5.94 (1H, d, J=6 Hz), 7.22 (1H, t, J=8 Hz), 7.40 (1H, d, J=8 Hz), 7.49(1H, t, J=8 Hz), 7.57 (2H, d, JS=8 Hz), 7.80 (1H, d, J=8 Hz)

Example 36

A solution of hydrogen peroxide in trifluoroacetic acid (1M, 0.32 ml) was added to a solution of6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano- 4,3-b!benzofuran(120 mg) in trifluoroacetic acid (2.5 ml) at 4° C. The mixture wasstirred at ambient temperature for 30 minutes and to the mixture wasadded water. The separated solid was collected and dried. The obtainedsolid was suspended in hot ethanol and to the mixture was added water.The mixture was cooled and the separated solid was collected to give6-(2,6-dichlorobenzoylamino)-3,4-dihydro-1H-thiopyrano 4,3-b!-benzofuran 2-oxide (70 mg).

mp: >250° C.; NMR (DMSO-d₆, δ): 3.10-3.20 (2H, m), 3.30-3.50 (2H, m),4.03-4.12 (2H, m), 7.28 (1H, t, J=8SHz), 7.40 (1H, d, J=8 Hz), 7.46-7.61(3H, m), 8.85 (1H, d, J=8 Hz)

The following compounds Examples 37 (1) to (3)! were obtained accordingto a similar manner to that of Preiaration 42 (1).

Example 37 (1)

6-(3-Amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: 197°-200° C.; NMR (CDCl₃, δ): 1.80-2.00 (4H, m), 2.60-2.78 (4H, m),4.26 (2H, br s), 6.80 (1H, d, J=8 Hz), 7.18 (1H, d, J=8 Hz),7.20-7.30(2H, m) 7.88 (1H, br s), 8.32 (1H, m)

Example 37 (2)

3-Acetyl-7-(3-amino-2,6-dichlorobenzoylamino)-2-methylbenzo b!furan

mp: >250° C.; NMR (DMSO-d₆, δ): 2.61 (3H, s), 2.79 (3H, s), 5.72 (2H,s), 6.87 (1H, d, J=8 Hz), 7.19 (1H, d, J=8 Hz), 7.33 (1H, t, J=8 Hz),7.78 (1H, d, J=8 Hz), 7.82 (1H, d, J=8 Hz)

Example 37 (3)

7-(3-Amino-2,6-dichlorobenzoylamino)-2,3-dimethylbenzo b!furan

mp: 245°-246.5° C.; NMR (DMSO-d₆, δ): 2.15 (3H, s), 2.39 (3H, s), 5.68(2H, br s), 6.83 (1H, d, J=8 Hz), 7.19 (2H, m), 7.30 (1H, d, J=8 Hz),7.72 (1H, d, J=8 Hz)

Example 38 (1)

To a mixture of6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100mg) and triethylamine (54 mg) in chloroform (3 ml) was addedchloroacetyl chloride (36 mg) under ice cooling. The mixture was stirredat ambient temperature for 2 hours, and then dimethyl aminehydrochloride (65 mg) was added to the mixture and additionally themixture was stirred for 12 hours. The mixture was washed with water andbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel eluting with(ethyl acetate: n-hexane=1:1) and the obtained oil was crystallized fromethanol to give 6-2,6-dichloro-3-(2-dimethylaminoacetylamino)benzoylamino!-1,2,3,4-tetrahydrodibenzofuran(62 mg).

mp: 207° C.; NMR (CDCl₃, δ): 1.79-2.00 (4H, m), 2.42 (6H, s), 2.59-2.77(4H, m), 3.15 (2H, s), 7.24 (2H, m), 7.40 (1H, d, J=8 Hz), 7.89 (1H, brs), 8.29 (1H, dd, J=1 and 8 Hz), 8.51 (1H, d, J=8 Hz), 9.99 (1H, br s)

The following compounds Examples 38 (2) to (6)! were obtained accordingto a similar manner to that of Example 38 (1).

Example 38 (2)

7-(2,6-Dichloro-3-dimethylaminoacetylaminobenzoyl-amino)-2,3-dimethylbenzob!furan

mp: 211.5°-213° C.; NMR (CDCl₃, δ): 2.15 (3H, s), 2.37 (3H, s), 2.41(6H, s), 3.13 (2H, s), 7.22 (2H, m), 7.40 (1H, d, J=8 Hz), 7.83 (1H, brs), 8.28 (1H, d, J=8 Hz), 8.51 (1H, d, J=8 Hz)

Example 38 (3)

6-2,6-Dichloro-3-(morpholin-4-yl)-acetylaminobenzoylamino!-1,2,3,4-tetrahydrodibenzofuran

mp: 252°-254° C.; NMR (CDCl₃, δ): 1.79-2.02 (4H, m), 2.60-2.78 (8H, m),3.23 (2H, s), 3.72-3.82 (4H, m), 7.25 (2H, d, J=6 Hz), 7.40 (1H, d, J=8Hz), 7.89 (1H, br s), 8.28 (1H, dd, J=6 and 6 Hz), 8.56 (1H, d, J=8 Hz),10.07 (1H, br s)

Example 38 (4)

3-Acetyl-7-(2,6-dichloro-3-dimethylaminoacetylamino-benzoylamino)-2-methylbenzob!furan

mp: 235°-236° C.; NMR (CDCl₃, δ): 2.42 (6H, s), 2.66 (3H, s), 2.79 (3H,s), 3.15 (2H, s), 7.35-7.40 (2H, m), 7.72 (1H, d, J=8 Hz), 7.90 (1H, s),8.32 (1H, d, J=8 Hz), 8.51 (1H, d, J=8 Hz)

Example 38 (5)

6- 2,6-Dichloro-3-bis(2-methoxyethyl)aminoacetyl-amino!benzoylamino!-1,2,3,4-tetrahydrodibenzofuran

mp: 168.5°-170.0° C.; NMR (CDCl₃, δ): 1.80-1.99 (4H, m), 2.60-2.68 (2H,m), 2.68-2.77 (2H, m), 2.88 (4H, t, J=5 Hz), 3.28 (6H, s), 3.44 (2H, s),3.50 (4H, t, J=5 Hz), 7.22-7.28 (2H, m), 7.38 (1H, d, J=8 Hz), 7.87 (1H,br s), 8.30 (1H, dd, J=1.5 and 7 Hz), 8.58 (1H, d, J=8 Hz)

Example 38 (6)

6-(2,6-Dichloro-3-ureidobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: 242°-244° C.; NMR (DMSO-d₆, δ): 1.71-1.98 (4H, m), 2.53-2.79 (4H,m), 6.51 (2H, br s), 7.20 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.43(1H, d, J=8 Hz), 7.82 (1H, d, J=8 Hz), 8.20-8.30 (2H, m)

Example 39 (1)

A mixture of6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100mg), methanesulfonyl chloride (120 mg) and triethylamine (162 mg) indichloromethane (3 ml) was stirred at ambient temperature for 2 hours.The reaction mixture was diluted with dichloromethane and washed with1N-hydrochloric acid, aqueous saturated sodium bicarbonate and brine.The solution was dried over sodium sulfate and concentrated in vacuo.The residual oil was crystallized from ethanol to give 6-2,6-dichloro-3-bis(methanesulfonyl)aminobenzoyl-amino!-1,2,3,4-tetrahydrodibenzofuran(87 mg).

mp: 237°-238.5° C.; NMR (CDCl₃, δ): 1.78-2.01 (4H, m), 2.57-2.80 (4H,m), 3.50 (6H, s), 7.23 (2H, d, J=6 Hz), 7.43 (1H, d, J=8 Hz), 7.50 (1H,d, J=8 Hz), 7.98 (1H, br s), 8.25 (1H, t, J=6 Hz)

The following compounds Examples 39 (2) to (5)! were obtained accordingto a similar manner to that of Example 39 (1).

Example 39 (2)

6-(3-Acetoxyacetylamino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: 225°-227° C.; NMR (CDCl₃, δ): 1.78-2.00 (4H, m), 2.24 (3H, s),2.58-2.77 (4H, m), 4.75 (2H, s), 7.20-7.29 (2H, m), 7.41 (1H, d, J=8Hz), 7.88 (1H, br s), 8.27 (1H, dd, J=6 and 6 Hz), 8.46-8.55 (2H, m)

Example 39 (3)

6-(2,6-Dichloro-3-methoxyacetylaminobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: 217° C.; NMR (CDCl₃, δ): 1.79-2.01 (4H, m), 2.60-2.78 (4H, m), 3.55(3H, s), 4.09 (2H, s), 7.24 (2H, d, J=6 Hz), 7.40 (1H, d, J=8 Hz), 7.90(1H, br s), 8.29 (1H, m), 8.52 (1H, d, J=8 Hz), 8.98 (1H, br s)

Example 39 (4)

7-(2,6-Dichlorobenzoylamino)-2,3-dimethyl-5-(morpholin-4-yl)carbonylaminobenzob!furan

mp: >250° C.; NMR (DMSO-d₆, δ): 2.10 (3H, s), 2.37 (3H, s), 3.38-3.50(4H, m), 3.57-3.60 (4H, m), 7.40-7.60 (4H, m), 7.87 (1H, s), 8.61 (1H,s)

Example 39 (5)

7-(2,6-Dichlorobenzoylamino)-2-methyl-3-(morpholin-4-yl)carbonylaminomethylbenzob!furan

mp: >250° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 2.48 (3H, s), 3.33 (4H, t, J=5Hz), 3.68 (4H, t, J=5 Hz), 4.45 (2H, d, J=6 Hz), 5.25 (1H, t, J=6 Hz),7.25 (1H, t, J=7 Hz), 7.30-7.45 (4H, m), 8.17 (1H, d, J=7 Hz)

Example 40 (1)

A mixture of6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100mg), aqueous 37% formaldehyde, sodium cyanoborohydride (70 mg) andacetic acid (5 drops) in acetonitrile (2 ml) was stirred at ambienttemperature for 3 hours. The reaction mixture was partitioned betweendichloromethane and aqueous saturated sodium bicarbonte. The organiclayer was separated, washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by preparative TLC onsilica gel and the obtained oil was crystallized from diisopropyl etherto give6-(2,6-dichloro-3-methylaminobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran(21 mg).

mp: 160°-162° C.; NMR (CDCl₃, δ): 1.78-2.00 (4H, m), 2.58-2.78 (4H, m),2.93 (3H, d, J=6 Hz), 4.52 (1H, m), 6.64 (1H, d, J=8 Hz), 7.18-7.30 (3H,m), 7.83 (1H, br s), 8.31 (1H, dd, J=1 and 8 Hz)

The following comopund was obtained according to a similar manner tothat of Example 40 (1).

Example 40 (2)

7-(2-Chloro-6-dimethylaminobenzoylamino)-2,3-dimethylbenzo b!furan

mp: 118°-119° C.; NMR (CDCl₃, δ): 2.15 (3H, s), 2.37 (3H, s), 2.87 (6H,s), 6.94 (1H, d, J=8 Hz), 7.04 (1H, d, J=8 Hz), 7.17-7.30 (3H, m),8.26-8.31 (2H, m)

Example 41

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1Msolution, 0.58 ml) was added to a solution of7-(2,6-dichloro-3-triisopropylsilyloxybenzoylamino)-2,3-dimethylbenzob!furan (221 mg) in tetrahydrofuran (2 ml) at 4° C. The solution wasstirred at 4° C. for 1 hour and concentrated in vacuo. The residue waspurified by column chromatography on silica gel and the obtained oil wascrystallized from diisopropyl ether to give7-(2,6-dichloro-3-hydroxybenzoylamino)-2,3-dimethylbenzo b!furan (152mg).

mp: 191.5°-193.5° C.; NMR (CDCl₃, δ): 2.14 (3H, s), 2.36 (3H, s), 5.78(1H, br s), 7.05 (1H, d, J=8 Hz), 7.20-7.31 (3H, m), 7.80 (1H, br s),8.26 (1H, d, J=8 Hz)

Example 42

A solution of 7-2,6-dichloro-3-(2-methoxyethyl)oxymethoxymethylbenzoylamino!-2,3-dimethylbenzob!furan (305 mg) in 10% methanolic hydrogen chloride (4.5 m.l) wasrefluxed for 1 hour. The reaction mixture was cooled and the separatedsolid was collected to give7-(2,6-dichloro-3-hydroxymethylbenzoylamino)-2,3-dimethylbenzo b!furan(217 mg).

mp: 258°-261° C.; NMR (DMSO-d₆, δ): 2.15 (3H, s), 2.39 (3H, s), 4.60(2H, d, J=5 Hz), 5.61 (1H, t, J=5 Hz), 7.21 (1H, t, J=8 Hz), 7.31 (1H,d, J=8 Hz), 7.57 (1H, d, J=8 Hz), 7.62 (lh, d, J=8 Hz), 7.80 (1H, d, J=8Hz)

Example 43

Aqueous saturated ammonium chloride (1 ml) was added dropwise to asuspension of6-(2,6-dichloro-3-nitrobenzoylamino)-1,2,314-tetrahydrodibenzofuran (150mg) and zinc (120 mg) in a mixture of tetrahydrofuran (1.5 ml) andethanol (1 ml). The mixture was diluted with chloroform and theinsoluble matter was filtered off. The organic layer of the filtrate wasseparated, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was crystallized from ethyl acetate to give6-(2,6-dichloro-3-hydroxyaminobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran(40 mg).

mp: 175° C. (dec.); NMR (DMSO-d₆, δ): 1.73-1.96 (4H, m), 2.54-2.68 (2H,m), 2.68-2.78 (2H, m), 7.15-7.25 (2H, m), 7.30 (1H, d, J=8 Hz), 7.40(1H, d, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.56 (1H, br s), 8.78 (1H, m)

The following compound was obtained according to a similar manner tothat of Prenaration 2 (1).

Example 44

7-(2,6-Dichloro-3-ethoxycarbonylmethoxybenzoylamino)-2,3-dimethylbenzob!furan

mp: 131°-133° C.; NMR (CDCl₃, δ): 1.32 (3H, t, J=7 Hz), 2.16 (3H, s),2.38 (3H, s), 4.29 (2H, q, J=7 Hz), 4.73 (2H, s), 6.88 (1H, d, J=8 Hz),7.20-7.27 (2H, m), 7.31 (1H, d, J=8 Hz), 7.80 (1H, br s), 8.28 (1H, d,J=8 Hz)

Example 45 (1)

A mixture of6-(3-acetoxyacetylamino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran(67 mg) and aqueous 1N-sodium hydroxide (0.5 ml) in a mixture ofdichloromethane (1 ml) and methanol (1 ml) was stirred at ambienttemperature for 1 hour. The mixture was partitioned between a mixture ofdichloromethane and ethanol (8:2) and water. The organic layer wasseparated, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was crystallized from ethanol to give6-(2,6-dichloro-3-hydroxyacetylamino-benzoylamino)-1,2,3,4-tetrahydrodibenzofuran(30 mg).

mp: 245°-249° C.; NMR (CDCl₃ :CD₃ OD=9:1, δ): 1.80-2.00 (4H, m),2.58-2.80 (4H, m), 4.20 (2H, s), 7.24 (2H, d, J=5 Hz), 7.41 (1H, d, J=8Hz), 8.20 (1H, t, J=5 Hz), 8.47 (1H, d, J=8 Hz)

The following compound was obtained according to a similar manner tothat of Example 45 (1).

Example 45 (2)

6-(2,6-Dichloro-3-methanesulfonylaminobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran.

mp: 202°-204° C.; NMR (CDCl₃, δ): 1.79-2.01 (4H, m), 2.59-2.78 (4H, m),3.08 (3H, s), 6.89 (1H, br s), 7.25 (2H, d, J=5 Hz), 7.43 (1H, d, J=8Hz), 7.73 (1H, d, J=8 Hz), 7.87 (1H, br s), 8.26 (1H, t, J=5 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 43 (1).

Example 46

7-(2-Amino-6-methylbenzoylamino)-3-(1-hydroxy-1-methylethyl)-2-methylbenzob!furan

mp: 127°-128° C.; NMR (CDCl₃, δ): 1.71 (6H, s), 1.80 (1H, s), 2.45 (3H,s), 2.56 (3H, s), 4.28 (2H, br s), 6.60 (1H, d, J=8 Hz), 6.66 (1H, d,J=8 Hz), 7.12 (1H, t, J=8 Hz), 7.20 (1H, t, J=8 Hz), 7.45 (1H, d, J=8Hz), 7.91 (1H, br s), 8.23 (1H, d, J=8 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 18 (1).

Example 47

9-Acetyl-6-(2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran

mp: 212°-214° C.; NMR (CDCl₃, δ): 1.75-1.95 (4H, m), 2.67 (3H, s), 2.73(2H, m), 2.90 (2H, m), 7.30-7.45 (3H, m), 7.72 (1H, d, J=7 Hz), 8.02(1H, br s), 8.38 (1H, d, J=7 Hz)

The following compound was obtained according to a similar manner tothat of Preparation 14.

Example 48

7-(2,6-Dichlorobenzoyl)-2,3,5-trimethylbenzo b!furan

mp: 143°-146° C.; MNR (CDCl₃, δ): 2.13 (3H, s), 2.29 (3H, s), 2.45 (3H,s), 7.30-7.50 (5H, m)

We claim:
 1. A compound of the formula: ##STR16## wherein R¹ ishydrogen, lower alkyl, an acyl group, amino, acylamino, nitro, halogenor hydroxy(lower)alkyl which may have one or more suitablesubstituent(s),R² is lower alkyl or acyl(lower)alkyl, R³ is hydrogen,lower alkyl, lower alkenyl, cyclo(lower)alkyl(lower)alkyl, halogen, anacyl group, acyl(lower)alkyl, acylamino, acylamino(lower)alkyl,acyl(lower)alkenyl, acyloxy(lower)alkyl,acyl(lower)alkylthio(lower)alkyl, amino(lower)alkyl, mono- (or di-)loweralkylamino, lower alkylthio(lower)alkyl, mono-(ordi)loweralkoxy(lower)alkyl which may have one or more suitablesubstituent(s), hydroxyimino(lower)alkyl which may have one or moresuitable substituent(s), hydroxy(lower)alkyl which may have one or moresuitable substituent(s), hydroxy(lower)alkylthio(lower)alkyl, loweralkyl substituted with heterocyclic group which may have one or moresuitable substituent(s), heterocyclic group which may have one or moresuitable substiutuents(s), or heterocyclicthio(lower)alkyl, in which R²and R³ may be linked together to form(1) lower alkylene which may haveone or more suitable substituent(s), (2) lower alkenylene which may haveone or more suitable substituent(s), or (3) a group of the formula:##STR17## wherein A¹ and A² are each lower alkylene which may have oneor more suitable substituent(s), and ##STR18## W is wherein R⁵ ishydrogen, or an acyl group, andm and n are each an integer of 0 or 1, Xis O Y is a group of the formula: --NHCO--, Z is aryl which may have oneor more suitable substituent(s), l is an integer of 1, and apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein Z is naphthyl which may have one or more suitablesubstituent(s), or a group of the formula: ##STR19## wherein R⁷, R⁸, R⁹and R¹⁰ are each hydrogen, halogen, lower alkyl, nitro, lower alkoxy, anacyl group, cyclo(lower)alkyl, mono-(or di- or tri)halo(lower)alkyl,acylamino, aryl, amino, hydroxyamino, mono-(or di-)lower alkylamino,aryloxy, aryl(lower)alkoxy, hydroxy, hydroxy(lower)alkyl which may haveone or more suitable substituent(s), heterocyclic group which may haveone or more suitable substituent(s), mono-(or di-)loweralkylamino(lower)alkyl or acyl(lower)alkoxy.
 3. The compound of claim1,wherein R² is lower alkyl, carboxy(lower)alkyl or protectedcarboxyl(lower)alkyl, R³ is hydrogen, lower alkyl, lower alkenyl,cyclo(lower)alkyl(lower)alkyl, cyclo(lower)alkylcarbonyloxy(lower)alkyl,halogen, lower alkanoyl, heterocyclic carbonyl(lower)alkyl, loweralkanoylamino, lower alkoxycarbonylamino(lower)alkyl, loweralkanoylamino(lower)alkyl, heterocyclic carbonylamino(lower)alkyl,carboxy(lower)alkenyl, protected carboxy(lower)alkenyl, loweralkanoyloxy(lower)alkyl, aroyloxy(lower)alkyl, protectedcarboxyoxy(lower)alkyl, protected carboxy(lower)alkylthio(lower)alkyl,amino(lower)alkyl, di-lower alkylamino, di-loweralkylaminocarbonyl(lower)alkyl, lower alkylaminocarbonyloxy(lower)alkyl,cyclo(lower)alkylaminocarbonyl(lower)alkyl, carboxy(lower)alkyl,protected carboxy(lower)alkyl, lower alkylthio(lower)alkyl, di-loweralkoxyphosphoryl(lower)alkyl, di-lower alkoxyphosphoryloxy(lower)alkyl,hydroxyimino(lower)alkyl, hydroxy(lower)alkyl which may have 1 to 3suitable substituent(s), hydroxy(lower)alkylthio(lower )alkyl, di-loweralkylaminocarbonyl(lower)alkyl, carboxy(lower)alkanoyloxy(lower)alkyl,lower alkoxy(lower)alkyl, hydroxy(lower)alkylaminocarbonyl(lower)alkyl,lower alkoxy(lower)alkylaminocarbonyl(lower)alkyl,aminocarbonyl(lower)alkyl substituted with heterocyclic group which mayhave 1 to 3 suitable substituent(s), heterocyclic(lower)alkyl,heterocyclic(lower)-alkylaminocarbonyl(lower)alkyl, heterocyclic groupwhich may have 1 to 3 suitable substituent(s)heterocyclicthio(lower)alkyl, or a group of the formula: ##STR20##wherein A³ is lower alkylene which may have 1 to 3 suitablesubstituent(s),R¹¹ is hydrogen or lower alkyl, and A⁴ is lower alkyleneor a group of the formula: ##STR21## wherein Q is phenylene which mayhave 1 to 3 suitable substituent(s) or cyclo(lower)alkylene which mayhave 1 to 3 suitable substituent(s), and o andare each an integer of 0or 1, in which R² and R³ may be linked together to form(1) loweralkylene which may have 1 to 3 suitable substituent(s), (2) loweralkenylene which may have 1 to 3 suitable substituent(s), or (3) a groupof the formula: ##STR22## wherein A¹ and A² are each lower alkylenewhich may have 1 to 3 suitable substituent(s), ##STR23## W is wherein R⁵is hydrogen, or an acyl group andm and n are each an integer of 0 or 1,Z is aryl which may have 1 or more suitable substituent(s).
 4. Thecompound of claim 3, whereinR³ is hydrogen, lower alkyl, lower alkenyl,cyclo(lower)alkyl(lower)allkyl, cyclo(lower)alkylcarbonyloxy(lower)altlo, halogen, lower alkanoyl, morpholinocarbonyl(lower)alkyl, loweralkanoylamino, lower alkoxycarbonylamino(lower)alkyl, loweralkanoylamino(lower)alkyl, morphol inocarbonylamino(lower)allkyl,carboxy(lower)alkenyl, protected carboxy(lower)alkenyl, loweralkanoyloxy(lower)alkyl, benzoyloxy(lower)alkyl, protectedcarboxyoxy(lower)alkyl, protected carboxy(lower)alkylthio(lower)alkyl,amino(lower)alkyl, di-lower alkylamino, di-loweralkylaminocarbonyl(lower)alkyl, lower alkylaminocarbonyl(lower)alkyl,carboxy(lower)alkyl, protected carboxy(lower )alkyl, loweralkylthio(lower)alkyl, di-lower alkoxyphosphoryl(lower)alkyl, di-loweralkoxyphosphoryloxy(lower)alkyl, hydroxyimino(lower)alkyl,hydroxy(lower) alkyl which may have 1 to 3 substituent(s) selected fromthe group consisting of protected carboxy, tri-halo(lower)alkyl,cyclo(lower)alkyl and phenyl, hydroxy(lower)alkylthio(lower)alkyl,di-lower alkylaminocarbonyl(lower)alkyl,carboxy(lower)alkanoyloxy(lower)alkyl, lower alkoxy(lower)alkyl,hydroxy(lower)alkylaminocarbonyl(lower)alkyl, loweralkoxy(lower)alkylaminocarbonyl(lower)alkyl, aminocarbonyl(lower)alkylsubstituted with thiadiazolyl having tri-halo(lower)alkyl,imidazolyl(lower)alkyl, pyridyl(lower)alkylaminocarbonyl(lower)alkyl,thiazolyl having lower alkanoylamino, imidazolylthio(lower)alkyl, or agroup of the formula: ##STR24## wherein A³ is lower alkylene which mayhave 1 to 3 substituent(s) selected from the group consisting ofprotected carboxy, tri-halo(lower)alkyl, cyclo(lower)alkyl andphenyl,R¹¹ is hydrogen or lower alkyl, and A⁴ is lower alkylene or agroup of the formula: ##STR25## (wherein Q is phenylene which may have 1to 3 substituent(s) selected from the group consisting of lower alkyland lower alkoxy, or cyclo(lower)alkyl which may have 1 to 3substituent(s) selected from the group consisting of lower alkyl andlower alkoxy, and o and p are each an integer of 0 to 1, in which R² andR³ may be linked together to form(1) lower alkylene which may have 1 to3 substituent(s), selected from the group consisting of lower alkyl,hydroxy and oxo, (2) lower alkenylene, or (3) a group of the formula:##STR26## wherein A¹ and A² are each lower alkylene which may have 1 to3 substituent(s) selected from the group consisting of hydroxy and oxo,##STR27## W is wherein R⁵ is hydrogen or an acyl group, andm and n areeach an integer of 0 or 1, Z is naphthyl which may have 1 to 3substituent(s) selected from the group consisting of lower alkyl, oxo,hydroxy, lower alkoxy, nitro and halogen,or a group of the formula:##STR28## wherein R⁷, R⁸, R⁹ and R¹⁰ are each hydrogen, halogen, loweralkayl, nitro, lower, lower aloxy, carbamoyl, protected carboxy,carboxy, benzoyl, cyclo(lower)alkoyl, tri-halo(lower)alkyl, loweralkanoylamino, ureido, phenyl, amino, mono- or di-lower alkylamino,hydroxyamino, phenoxy, phenyl(lower)alkoxy, hydroxy,hydroxy(lower)alkyl, pyrroyl which may have 1 to 3 lower alkyl, loweralkanoyloxy(lower)alkanoylamino, morpholino(lower)alkanoylamino, loweralkoxy(lower)alkanoylamino, hydroxy(lower)alkanoylamiino,di-(lower)alkylamino(lower)allkyl, protected carboxy(lower)alkoxy,di-(lower)alkylamino(lower)alkanoylamino, lower alkysulfonyamino, orbis(lower alkoxy(lower)alkyl)amino(lower)alkanoylamino.
 5. The compoundof claim 3, wherein Z is a group of the formula: ##STR29## wherein R⁷ ishalogen, lower alkyl, nitro lower alkoxy, carbamoyl, carboxy, protectedcarboxy, lower alkoxy, amino, phenoxy or phenyl(lower) alkoxy,R⁸ ishydrogen, halogen or lower alkyl, R⁹ is hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy, hydroxy(lower)alkyl, nitro, amino, loweralkanoylamino, hydroxyamino, lower alkylamino, loweralkanoyloxy(lower)alkanoylamino, morpholino(lower)alkanoylamino, loweralkoxy(lower)alkanoylamino, pyrroyl which may have 1 to 3 lower alkyl,hydroxy(lower)alkanoylamino, di-lower alkylamino(lower)alkyl, protectedcarboxy(lower)alkoxy, lower alkysulfonylamino, or di-loweralkoxy(lower)alkylamino(lower)alkanoylamino, R¹⁰ is hydrogen, halogen,lower alkyl, nitro, lower alkoxy, benzoyl, cyclo(lower)alkyl ortri-halo(lower)alkyl.
 6. The compound of claim 5, whereinR² is loweralkyl, R³ is hydroxy(lower)alkyl,cyclo(lower)alkylaminocarbonyl(lower)alkyl, protectedcarboxy(lower)alkyl, hydroxy(lower)alkylaminocarbonyl(lower)alkyl, loweralkoxy(lower)alkylaminocarbonyl(lower)alkyl, carbonyl(lower)alkyl whichmay have one or more suitable substituent(s), loweralkylaminocarbonyl(lower)alkyl which may have one or more suitablesubstituent(s) or a group of the formula: ##STR30## wherein A³ is loweralkylene, R¹¹ is hydrogen andA⁴ is lower alkylene, and Z is a group ofthe formula: ##STR31## wherein R⁷ is halogen or lower alkyl, R⁸ ishydrogen,R⁹ is hydrogen, di-lower alkylamino(lower)alkanoylamino, loweralkanoylamino, amino, lower alkoxy(lower)alkanoylaamino,hydroxy(lower)alkanoylamino, hydroxyamino, lower alkoxy or hydroxy, andR¹⁰ is halogen or lower alkyl.
 7. The compound of claim 1, wherein R³ ishydroxy(lower)alkyl, or a group of the formula: ##STR32## (wherein A³ islower alkylene, R¹¹ is hydrogen, andA⁴ is lower alkylene) andZ is agroup of the formula: ##STR33## (wherein R⁷ is halogen or lower alkyl,R⁸ and R⁹ are each hydrogen, and R¹⁰ is halogen or lower alkyl).
 8. Thecompound of claim 1, whereinR³ is protected carboxy(lower)alkyl, and Zis a group of the formula: ##STR34## (wherein R⁷ is halogen or loweralkyl, R⁸ and R⁹ are each hydrogen, andR¹⁰ is halogen or lower alkyl).9. The compound of claim 1, whereinR³ iscyclo(lower)alkylaminocarbonyl(lower)alkyl, and Z is a group of theformula: ##STR35## (wherein R⁷ is halogen or lower alkyl, R⁸ and R⁹ areeach hydrogen, andR¹¹ is halogen or lower alkyl).
 10. A pharmaceuticalcomposition which comprises, as an active ingredient, a compound ofclaim 1 or a pharmaceutically acceptable salt thereof in admixture withpharmaceutically acceptable carriers or excipients.
 11. A method for theprophylactic and/or the therapeutic treatment of diseases caused byabnormal bone metabolism which comprises administering a compound ofclaim 1 or a pharmaceutically acceptable salt thereof to a human beingor an animal.